Comments on Draft Guidances Relating to the Regulation of Human Cells, Tissues, or Cellular or Tissue-Based Products

18. january 2016 at 7:00 | Veronika Valdova, ARETE-ZOE |  Medicine & Pharmacy
I wish to comment on the concerned draft guidance and propose introduction of certain measures that would facilitate informed decision-making by stakeholders involved. All participants in the system need reliable and accurate information to make better treatment decisions: patients who consider stem cell treatments, healthcare professionals who care for these patients before and after such treatment, and payers, who may or may not wish to include these therapies in their programs depending on their benefits, risks, and cost-effectiveness.

The Helsinki Declaration says on unproven Interventions in Clinical Practice:

In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorized representative, may use an unproven intervention if in the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available. (Art. 37)

Most stem cell interventions are not reimbursed by insurers. Most of the time, patients have to pay for these treatments themselves. Patients are making decisions based on information they can find in public domain. Currently, it is very difficult to accurately evaluate the benefit:risk profile of stem cell treatments. Because procedures under 21 CFR part 1271 (CGTP) do not qualify as studies, treatment outcomes of these interventions are never made available to the public.

Interventions offered by establishments under 21 CFR part 1271 (CGTP) rely on studies that have already been done and published, as well as their own empirical experience from own medical practice. Brief overview of registered studies and published studies illustrate the scope and extent of the information gap on stem cell treatments and their outcomes.

To facilitate informed decision-making by patients, healthcare professionals, and insurers, I am suggesting creation of a registry into which information on stem cell interventions conducted under 21 CFR part 1271 would be reported. To make such undertaking worthwhile, the anonymized dataset would have to include indication, type of treatment, and treatment outcome. Not only this would greatly benefit patients, who would be able to make truly informed choice for themselves; this registry could also benefit healthcare professionals who would be able to compare stem cell interventions to other existing therapies.

In total, 5,298 studies conducted with stem cells globally as of January 7, 2016 ( Most studies are conducted in highly regulated markets in the U.S. and in Europe. Other popular destinations include China, Iran, Israel and Middle America.

Stem cell studies by recruitment status as of January 7, 2016 (

Conditions treated
The register lists wide variety of conditions studied in a manner that is difficult to assess. Many conditions are listed under wide variety of terms, often overlapping, some low level, and others very general and high level. It is therefore difficult to judge whether a study intervention should be at all included in a specific evaluation without detailed scrutiny of the study objectives and design. This task is challenging even for an experienced biomedical researcher, and virtually impossible for a non-healthcare professional.

Stem cell studies by conditions treated, August 2015.

Availability of study results as of January 7, 2016 (

Funders of studies that involve stem cells as of January 7, 2016 (


Vast majority of stem cell studies are interventional. The database does not allow the researcher to filter out studies where stem cells were used as the intervention, compared to study of other - non-stem cell - interventions studied on patients who previously received stem cells or other type of studies that do not study the efficacy and safety of stem cell intervention themselves.

Type of studies that involve stem cells as of January 7, 2016 (

Studies by phase as of January 7, 2016 (
Majority of stem cell research is in early phases of development. This involves lot of ambiguity and uncertainty for those undergoing such treatments, as well as for their regular healthcare providers and payers.

Number of patients enrolled in studies that involve stem cells as of January 7, 2016 (

Publications, publication bias and multiple publication bias

It is very difficult to assess the true value of stem cell intervention for a particular diagnosis based on information available in public domain, i.e. information from registries ( and WHO ICTRP) and published scientific literature. Most studies do not disclose results to the public, or do so with long delays. Publication bias and multiple publication bias makes certain results difficult to appropriately evaluate.

Simple search for stem cells in PubMed returns about 245,000 results. Of these, about 139,000 describe experience in humans. About 4,200 of the identified published papers are published clinical trials. The following examples illustrate how poorly information in public domain represents research that has been done.
Example: Amyotrophic Lateral Sclerosis (ALS, Aran-Duchenne Muscular Atrophy, Gehrig's Disease, Lou Gehrig's Disease)
  • 36 studies ("stem cells" & Condition: "ALS")
  • Of these 36 studies, 32 are interventional, 3 observational and 1 expanded access
  • None of the identified studies have any results posted in the registry
  • Enrollment: Interventional ALS studies - 805 patients in total; expanded access - 0; observational studies - 1185 (1000, 160 and 25).
  • Of these 36 studies, 10 were ever published in scientific literature, some multiple times.
  • The same studies can be found in PubMed.
Publication of studies involving "stem cells" and condition "Amyotrophic Lateral Sclerosis"

Example: Sickle Cell Anemia (Thalassemia)
  • 46 studies ("stem cells" & Condition: "sickle cell anemia")
  • Of these 46 studies, 39 are interventional and 7 observational
  • Three (3) of the identified studies have results posted in the registry
  • Enrollment: Interventional studies - 1066 patients; observational studies - 376 + 1 unlimited
  • Of these 46 studies, 7 were ever published in scientific literature, some up to 3 times:
  • PubMed search returns 22 human clinical trials for this particular diagnosis and stem cells. In total, 369 hits for "stem cells" AND "sickle cell anemia" mainly show results from animal and in vitro studies.
Publication of studies involving "stem cells" and condition "Sickle Cell Anemia"

Stem cell therapies potentially offer great benefits to patients whose current options are either limited or non-existent. Some patients are willing to undergo new, experimental and unproven therapies, to take advantage of this cutting-edge research. These people are taking all the risks associated with novel therapies and procedures upon themselves.

To protect the interests of patients, and to support innovation in this rapidly developing field of medicine, it would be wise to facilitate substantial improvement of the information environment, and to provide all parties involved with the information they need to make better treatment decisions.

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