I’m continuing to document of all clinical cases reports on complications of cell therapy with focus on regenerative medicine. I’m trying to capture all published autopsy or pathology reports. I believe, such database will equip professionals with a knowledge and allow to avoid mistakes in future translation of cell therapies. Today, I’m going to highlight the case, published online few days ago in Experimental Clinical Transplantation journal. You can find full text here. It was not the case of “stem cell tourism”, but IRB-approved clinical study (trial registry ID was not provided), conducted in academic medical center in Iran.

Briefly, 25 months after intravenous infusion of fetal liver-derived cells for experimental treatment of type 1 diabetes, patient was presented to neurologist with severe frontal headaches, vision disturbances and vomiting. Tumor-like mass was identified by CT in frontal lobe of the brain. Patients underwent neurosurgery and was diagnosed with transitional meningioma (benign tumor). Patient was discharged from the hospital 5 days after surgery. Tumor, patient’s blood and fetal liver cells were genetically tested:

Transplanted fetal HSCs, patient’s peripheral blood cells, and tumor cells were compared with a PCR using highly polymorphic microsatellite markers and PCR with specific primers for amelogenin homologous gene located on X and Y chromosomes. Genomic DNA was extracted from the patient’s blood samples and from the tumor tissue using standard protocols.

Unfortunately, the authors did not provide 100% evidence for tumor origin from transplanted fetal cells, but they have found DNA in the tumor, which was different from patient’s DNA:

Analysis of DNA obtained from the blood and tumor cells with 6 microsatellite markers which are listed in Table 1, demonstrated that the allele size for 5 markers were different from the DNA originated from the patient’s blood sample and the DNA extracted from the tumor. The number of alleles detected in the tumor originated from nonhost cells indicated the presence of more than 1 cell population in the tumor. Although the possibility of genomic instability in tumor remains as an alternative cause for these differences, it is more likely that the tumor had not originated from recipient cells.

The cell product was derived from 6-12-weeks aged aborted fetuses and cryopreserved for future infusions. The authors indicate that ~20% of cells were “recognized” as hematopoietic stem cells. Infused cell dose was 35-55 millions.

This is the first case report of tumorigenesis from systemically infused fetal cells. In previously reported cases, cells were delivered locally. I wish, more sophisticated genetic analysis would be performed for confirmation of tumor cell origin. I’d encourage you to read this report and discuss here. Also, you may be interested in contacting the authors about details of their genetic testing.

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On conditional approval of cell therapy products

by Alexey Bersenev on December 20, 2015 · 0 comments

in regulation

As you may know, about 2 years ago Japan has passed a new law for regulation of Regenerative Medicine. Under this law, the regulatory pathway for commercial cellular products is significantly accelerated by skipping of typical “Phase 3 trial” and allowance of marketing authorization after demonstration of safety and some (minimal) signs of efficacy (Phases 1/2). In this “accelerated scheme” the cell therapeutic candidate will be available to patients faster and company will able to generate profit and survive. It is important to keep in mind that this accelerated approval is conditional – in the next few years after market authorization, company-developer obligated to provide clinical data on efficacy. If there will be strong evidence for the efficacy, product will stay on the market. Professionals were watching this regulatory change in Japan with great interest and, most of us are very sympathetic of this approach.
Two years later, in September of 2015, the new Regenerative Medicine law yielded the first results – two cell products were approved on Japanese market. The first product is TemCell (by JCR Pharmaceuticals) – allogeneic mesenchymal stromal cells for GVHD. The second product is HeartSheet (by Terumo) – autologous skeletal muscle cells for heart failure. Two months after market authorization, both product have received price tag and reimbursement decision. TemCell is priced ~ $115,000 – $170,000 USD (depending on total number of doses infused) and HeartSheet is priced ~ $120,000 USD. Depending on insurance plans, Japanese patients will still pay out of pocket anything between 5% to 30% of the product price.

10 days ago, I was really surprised to see critical editorial in Nature journal about these milestones in new Japanese regenerative medicine regulation. The editorial called Japanese regulation as “unproven system to make patients pay for clinical trials“. Overall, tone of the article is negative:

Biotech companies in other countries are keen on the idea and have pushed their own regulatory bodies to follow Japan’s lead. This is a bad move. Regulatory agencies around the world should resist pressure to create such fast-track systems, at least until Japan has proved that its system works. That will take time. The country will have to demonstrate that its health-care system can withstand the costs of the new regenerative-medicine treatments, and that patients do not feel cheated.

First of all, I’d like to argue, that using term “clinical trial” after marketing authorization is not correct. It is not trial anymore. Patients do not pay for drugs that they received in clinical trial. And of course it is unproven at the moment, because the whole point of new legislation was to test whether system will prove itself to be effective and beneficial.

I don’t understand why patient may feel cheated, if they told about pricing/ reimbursement prior to therapy and were explained what conditional approval really means. I believe, patients able to make wise conscious decision, based on provided information. It is responsibility of product manufacturer to provide all necessary information.

I also don’t understand why if some other country would follow Japan’s path, “this is a bad move”? Aren’t governmental agencies of other countries competent and capable of making such decision? Who is Nature’s editorial author to judge? By the way, Japan did not invent a wheel here. There are few countries, which pioneered the system of conditional approvals long time before Japan. South Korean KFDA was the first to implement regulatory conditional approval system for cell products more than a decade ago (even thought, not exclusively for cellular products). Since 2001, S. Korea approved ~18 cell products on the market, most of them conditionally. Brazil, Canada and Europe have accelerated conditional approval systems in place. For example, dendritic cell-based cancer vaccine Hybricell was approved in Brazil in 2005 conditionally. Stem cell drug Prochymal was approved in Canada in 2012, conditionally. Finally, European EMA has a conditional market authorization option. All these conditional approval systems more or less similar. So, I’d argue that more likely Japan learned from other countries experience, and first of all, from South Korea.

It is not very clear right now how successful these conditional approval systems. I was trying to find any information about nearly 15-years old history of conditional approvals in S. Korea. There is almost zero publicly available information in English. However, I was able to find one failure on condition out of 18 approvals. Lymphokine activated killers product Inno-LAK (by Innomedisys) was approved conditionally by KFDA in 2007 for lung cancer. The company failed to provide additional clinical data and product was pulled off market in 2012. Based on what I’ve learned about S. Korean cell products approval, the system works quite well.

I’d also argue, that we don’t have very good example of efficient regulatory system in cell therapy/ regenerative medicine, from which both patients and product developers will benefit. So, why Nature’s editorial positions conventional FDA drug approval system as the best? FDA has a history of failures as well. Some FDA approved drugs were recalled from the market due to toxicity, some weren’t that efficacious as at point of approval. Weren’t those patients feeling cheated then by FDA’s system, which suppose to guarantee safety and efficacy? Also, I saw some articles, which argue that current (very lengthy and expensive) FDA regulatory system may not be sustainable for commercial cell therapy developers.

So, at this point, we do not know which regulatory system will work better for cell therapy/ regenerative medicine products. Neither Western (aka FDA) nor Asian (aka Korean/ Japanese) systems yet proved to be very efficient and beneficial for cell therapy field. Let’s wait one more decade to judge. As cell therapy trialist and developer I’m very happy about one thing here – right now we are witnessing unique experiment, where few countries simultaneously testing different regulatory frameworks for cell-based products. I’m eagerly awaiting results of this experiment. I’m very happy to see that Japan is moving fast. They will find out faster if the proposed law will work successfully. Other jurisdiction rather than go for “trial and error” may watch and adopt the most successful model.

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Starting from 2014, I was trying to capture results of clinical studies in cell therapy. Today, I’d like to share some results of this attempt. I decided to narrow down my analysis to regenerative medicine, since most of cell-based therapies with published results belong to this category.

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Inclusion criteria and definitions

  1. Clinical study defined as any study, which involves administration of alive cells as therapy in human and includes more than 3 subjects. It may include: registered clinical trials and “other human studies”.
  2. Analysis of published clinical trials could be interim (trial is not completed), final (trial is completed) or retrospective (post hoc analysis, long-term outcome).
  3. “Other clinical studies” may include (i) cohort studies, (ii) case series, (iii) clinical cases (3 subjects or more) and (iiii) undefined reports. “Other clinical studies” are not registered in clinical trial databases or could not be ID’d. Reports of compassionate use or hospital exemption could belong to both categories – registered as trial or have no ID.
  4. All published in medical literature reports of studies results, indexed in PubMed database.
  5. Regenerative medicine is defined (for the purpose of this analysis) as administration of alive cells to replaces or regenerates human cells, tissues or organs, to restore or establish normal function.
  6. Results of any clinical study, appeared in PubMed and/or journal web-site in the period between Jan. 1, 2014 to December 31, 2014.
  7. Mesenchymal stromal cells as immunomodulators were included in the analysis, because of multiple mechanisms of action, including tissue repair (example: GVHD)

Exclusion criteria

  1. Conference reports, companies press releases and mass media mentions.
  2. Clinical cases – reports, which describe less than 3 cases.
  3. Studies, which only describe design of the trial, but not results.
  4. Reviews.
  5. Other than “regenerative medicine” studies, which include cellular immunotherapies with immune cells in oncology, hematopoietic cell transplantation in hematology.

Search strategy
I set very loose filter for search of clinical studies results by using PubMed database with query “stem cell”. I receive notifications about new publications from this query via RSS feed. “Stem cell” query captures about 50-100 publications daily, <1% of them are clinical studies. I did random check to assess RSS feed accuracy and confirmed that it captures everything. I find that such filter allows to capture the most (if not all) clinical studies, related to cell-based therapies (by any type of cells) in regenerative medicine.  I also compared “stem cell” filter with “cell therapy” and some others. A stronger filter in PubMed – “stem cell” + “clinical trial” (check box), misses >90% of clinical studies.

Total number of studies and data capture

  • I was able to identify 116 clinical studies, which involve administration of cells as regenerative medicine.
  • Reports of cell-based regenerative medicine clinical studies results appear with a rate of 1 every 3 days.
  • I captured link to original publication, trial ID (if any), indication, country, number of subjects, type of cells, cell manipulations and some other additional information.
  • You can look at sample of raw data here.
  • 59 of 116 studies (~51%) did not have indication to any clinical trial ID.
  • 59 registered clinical trials IDs were identified in 57 published studies (2 studies described 2 registered trials).
  • About 80% of all trials were registered in NCT database (ClinicalTrials.gov).

Demographics
A great variety of countries published results of clinical studies in 2014. The biggest number of reports came from China. US was the second biggest contributor. I summarized major contributing countries (more than 4 reports) in this figure:

RMresults14_countries

Cell types
As one may predict, Mesenchymal Stromal Cells (MSC) was the major cell type (35%) in cell-based regenerative medicine clinical studies. Mobilized hematopoietic stem/progenitor cells (HPC-A) and bone marrow mononuclear cells (BM MNC) were another popular type of cells for tissue regeneration. Interestingly, 2 reports were about results of studies, involved embryonic stem cell-based (ESC) products. Few studies used 2 different types of cells cell simultaneously or concurrently.

RMresults14_cells

Results interpretation
I loosely judged all results of clinical studies as (1) positive, (2) mixed/ inconclusive and (3) failed.
Positive are the results, reported no safety and feasibility concerns and/or provided at least some evidence of efficacy.
Mixed/ inconclusive results included:

  • end points are defined, but were not analyzed/ described in report (example)
  • efficacy end points were not defined or different end points were reported (example)
  • some end points were met, but some missed (example)
  • only some subsets of patients responded – highly depends on approach to analysis (example)
  • number of patients is too low to conclude efficacy (example)
  • efficacy declined or deterioration observed in different time points (example)

Failed studies were considered, based on termination of studies due to safety issues, lack of feasibility and/ or lack of efficacy. Failed efficacy usually reported by authors as lack of difference between control group (example: placebo) and experimental (“cells”) group. Few trials were not described as failed by authors, but judged as such by me, based on lack of significance between groups and missed end points.

The first figure shows total number of positive, mixed/ inconclusive and failed studies from analysis of all reported studies (116):

RMresults14_total

Next, I looked at only registered clinical trials and broke it down by phases – 1, 1/2, 2, 2/3 and 3:

RMresults14_phases

Only one trial is failed in phase 1 and almost 90% of them reported as “positive”. The only trial, which failed in phase 1 was designed with efficacy end points. There were no trials, which failed safety. A number of mixed/inconclusive and failed trials were increased from phase 1 to 2/3. Because efficacy of therapy is usually assessed in phase 2 trials, studies labeled as “phase 1/2” are not necessarily included efficacy end points. Despite lack of any controls many studies concluded by authors as “positive” or “promising”. Placebo control was very rare. Most controls include: (i) historic, (ii) baseline and (iii) standard therapy.

Limitations of analysis

  1. The data are not validated by independent researcher.
  2. Definitions, inclusion and exclusion criteria, data interpretation were set by me and could be subjective.
  3. Thorough analysis was limited by the lack of access to some publications (I’d estimate ~10%).
  4. Only PubMed database was used for data capture.
  5. Results of many studies were very hard to interpret, because end points were not defined or/and were not reported, absence of control groups, low number of subjects. Mixed/ inconclusive results category is especially difficult to analyze. It could be interpreted differently by different people.

It was a snapshot of some data that I was able to capture in 2014. Please feel free to give me feedback and discuss these data in comments. I’m open to suggestions and collaboration.

How to cite:
Bersenev Alexey. Results of regenerative medicine clinical studies from 2014. CellTrials blog. March 1, 2015. Available: http://celltrials.info/2015/03/01/results-regenmed-studies-2014

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Trends in cell therapy clinical trials 2011 – 2014

February 14, 2015

Post updated on Feb. 17, 2015 Today I’m sharing some of my data for the last 4 years. This is a snapshot of trends in cell therapy trials from 2011 to 2014. This year, I’m planning to make few posts on cell therapy trends. I’d like to analyze some trends in mesenchymal stromal cells, adipose […]

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Cell therapy clinical trials – 2014 Report

January 22, 2015

This is 2014 report of registered cell therapy clinical trials. Every year I give a snapshot of some tracked data, captured from international clinical trials databases. You can see previous annual reports here. Definitions and criteria I tracked clinical trials which fall in definition of cell therapy: administration of living cells in human with therapeutic […]

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Embryonic stem cells in cerebral palsy – results of clinical study from India

January 11, 2015

One clinical study, which was released 2 weeks before Christmas holidays captured my attention (but not attention of mass media). One of the most scandalous Indian “stem cell tourism” clinic Nutech Mediworld published(!) results of the study, which evaluates embryonic stem cell transplantation in children with cerebral palsy. Yes, you’re reading it correctly – embryonic […]

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Cell therapy clinical trials failures in 2014

January 4, 2015

Today, I’d like to highlight the most interesting, in my opinion, clinical trials failures, reported in 2014. As field is moving to efficacy (Phase 2) trials, we are starting to see more failures. In this overview, I’m going to focus on efficacy results. I hope we can learn a lot from these failures and avoid […]

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Top 10 cell therapy clinical studies in 2014

January 2, 2015

At the end of the year I analyze results of clinical studies in cell therapy. Today, I’d like to highlight 10 most significant, in my opinion, clinical studies with published results. Taking in account excellent safety profile of most cellular therapies, I was trying to focus on efficacy and long-term outcomes. Do cells really work? […]

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Cell therapy highlights from #ASH14

December 8, 2014

Annual 56th meeting of American Society for Hematology (ASH) is about to finish in San Francisco. I was following conference via twitter and I was amazed by stream of tweets – very good tweets, high value tweets, unpublished data tweets, 1 tweet per second! There was no “scientific tweets”, but almost all were “clinical”. Here, […]

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Some thoughts on results of NeoStem cardiac cell therapy trial

November 19, 2014

In the last two days I was involved in lively twitter discussions about the results of Phase 2 PreSERVE-AMI clinical trial, sponsored by NeoStem. Unfortunately, interpretation of results divided professionals for two camps – (1) trial is failed and (2) trial is successful. Why did it happen? Maybe the truth somewhere in the middle? I’d […]

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