January 2016

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I wish to comment on the concerned draft guidance and propose introduction of certain measures that would facilitate informed decision-making by stakeholders involved.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 (ClinicalTrials.gov). 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 (ClinicalTrials.gov).

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 (ClinicalTrials.gov).

Funders of studies that involve stem cells as of January 7, 2016 (ClinicalTrials.gov).


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 (ClinicalTrials.gov)

Studies by phase as of January 7, 2016 (ClinicalTrials.gov)
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 (ClinicalTrials.gov)

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 (ClinicalTrials.gov 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 CT.gov 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 CT.gov 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.

FDA inspections 2008-2015

11. january 2016 at 7:00 | Veronika Valdova, ARETE-ZOE

In the last 7 years, in the period from January 2008 to March 2015, the FDA conducted more than 133,000 inspections. About half of this figure concerned foodborne biological hazards, Food composition, standards and labeling, and food and color additives. About 11,000 of all inspections, or 9%, related to drug quality assurances, and only a tiny fraction (362) identified unapproved and misbranded drugs.

Inspections are classified to reflect the compliance status of a firm. Classifications are based upon findings identified during an inspection and Agency review for compliance.

Bioresearch Monitoring3 298
Blood and Blood Products8 123
Colors and Cosmetics Technology773
Compliance: Devices11 822
Drug Quality Assurance10 902
Food and Color Additives Petition review3 619
Food Composition, Standards, Labeling6 490
Foodborne biological hazards50 370
Human, cellular, tissue and gene therapies3 850
Interagency cooperative activities1
Molecular biology and natural toxins28
Monitoring of marketed animal drugs, feed and devices12 293
Pesticides and chemical concominants4 766
Postmarket assurance: devices6 162
Postmarket surveillance and epidemiology542
Pre-approval evaluation of animal drugs an food additives190
Project evaluation: devices2 225
Unapproved and misbranded drugs362
Vaccines and allergenic products402
Inspection classification database

The beauty of a New Years Eve duty at A&E

4. january 2016 at 7:00 | Veronika Valdova, ARETE-ZOE |  Risk Management

A while ago I was invited to comment on training procedures pertaining to triage of patients with mental health issues at a major UK hospital. This particular case study involves a nursing assistant who in his or her limited capacity has to decide how to handle each specific case many times a night.

The hospital asked its staff a simple question:

"In your capacity do you feel you have enough training and coping mechanisms in place to safeguard yourself and a patient experiencing mental- ill health?"

After considerable time spent interviewing staff over their knowledge and understanding of existing laws, regulations and procedures, the simple and short answer is "No".

This particular A&E admits about 320-400 new patients a day, of whom about 20 are patients with some kind of mental health problem. This figure does not include patients with dementia. Some of these patients are violent as a result of alcohol or drug abuse. The hospital also has to handle patients with long-term previously diagnosed psychiatric conditions, new onset psychiatric conditions, including drug-induced psychoses, erratic behavior and seizures resulting from trauma, poisoning, adverse drug reactions or metabolic conditions or other underlying disease, and distressed victims of crime such as domestic violence or sexual abuse, and victims of human trafficking.

Clear and understandable instructions for staff are necessary to comply with all applicable laws, regulations, instructions, and with hospital policy.

The following intriguing questions for handling these cases shall be promptly resolved by management of the hospital, and appropriate procedures including training shall be circulated to people on wards to minimize any liability caused by improvisation and human error.
  • What is the standard procedure for obtaining informed consent from patients who are conscious and able (but unwilling) to give consent with admission for examination and treatment?
  • What is the standard procedure for obtaining informed consent in situations when the patient is unconscious, incapacitated, disoriented but conscious, incapable of giving consent and non-aggressive, aggressive and uncooperative?
  • What are the symptoms a nursing assistant need to watch out for before he/she shall escalate the matter and ask someone to decide?
  • What are the roles and responsibilities for making decisions on such cases?
  • Who is the correct person to go to if the initial assessment indicates that the patient is a mental health case?
  • When a nursing assistant is allowed to use force, and what are the appropriate techniques? Do they need to record in patient chart that force had to be used, and what technique was applied? What if the patient becomes injured during the procedure?
  • How does a nursing assistant know who is the patient's next of kin? How does the hospital determine who is the most appropriate person to talk about the patient's health, especially if his/her family status is less than straightforward? The hospital already experienced cases of family feud and honor killing. The city is also a major human trafficking hub.
  • How does staff communicate with other persons who came in with the patient (police, neighbors, family members, coworkers)?
  • Who is responsible for accepting restraining orders, warrants, and similar measures, and how does a nursing assistant find out? Is this listed in the patient documentation, or is this communicated during a handover brief? Does the note on file refer to applicable internal procedure?
  • Does the hospital separate appropriately guarded ward for patients who can endanger themselves, other patients and staff?
  • How does the hospital ensure that distressed victims of crime, especially domestic violence and rape, are not held together with potentially dangerous individuals in the same "mental health" ward?
  • What is the protocol for the treatment of victims of rape to make sure forensic evidence is not destroyed in the process?
  • If drug abuse is suspected, especially substances such as bath salts, what is the correct procedure for obtaining and handling samples? Does the hospital use LC/GC detection equipment where the samples can be examined quickly?
  • What if poisoning or drug-induced psychosis is suspected, including adverse drug reactions to Rx drugs and Rx drug interactions?
  • Who is responsible for triage of these patients?
This list is by no means exhaustive. It is, however, illustrative of some of the challenges first line staff faces on busy nights.

What constitutes a successful clinical trial?

2. january 2016 at 19:08 | Veronika Valdova, ARETE-ZOE |  Medicine & Pharmacy

NHLBI has issued the first in a series of Requests for Information (RFIs) to solicit input from its stakeholders on ways to optimize the clinical trials enterprise:

"Characteristics of a successful clinical trial (recognizing that a clinical trial can be assessed in a variety of ways, including but not limited to advancing science and completing a trial on time and on budget)"

Risks to project success often result from a sequence of logically dependent decisions and actions by independent entities that operate within a clinical trial. Any incorrect assumptions made earlier in the process of drug discovery and pre-clinical development about drug characteristics and mode of action, which cannot be independently verified or remain concealed or unrealized through subsequent development phases can contribute to a patient casualty.[1]

Information on products is heavily dependent on clinical studies generated by the industry or funded by the industry. Non-registered studies, unpublished studies, and delays in registration of studies create an important disconnect between produced results and perceived findings. Registration of clinical studies improved the situation considerably over the last 15 years but did not resolve the selective information flow from the industry to medical professionals (publication bias and multiple publication bias). Multiple publication of a positive study amplifies such information, creating a false positive incentive for prescription (widely publicized anecdotal finding) whilst suppression of negative studies (publication bias) limits access to potentially crucial information for healthcare professionals.[2]

Very varied design of clinical studies makes them difficult to interpret by the target audience (regulators and healthcare professionals). Industry can opt for wide variety of designs to prove value of the product. Uncertainty about risks plays in favor of the producer especially after the drug has reached the market. Intentional avoidance of the producer to design and conduct studies empowered to define risks to patients, and disclose and mitigate these risks accordingly, can be interpreted as intentional interaction with uncertainty.[3]

Redefinition of trial success vs. failure would profoundly affect the value of trial results to other stakeholders, i.e. clinicians, investors, payers, and patients.

Independent assessment of "value" of a clinical trial would enable researches, medical professionals, investors and payers to make valid and reliable assessments of large numbers of differently designed trials. Rigorous assessment of "value" of a trial would also provide incentive to trial sponsors to prioritize resources toward trials, which provide clinically meaningful information, and improve their overall metrics. Trials without posted results have no meaning and no value for the consumer.
  • Are questions posed by the trial clinically relevant? The use of surrogate endpoints in trials should always be compared against real life data (EHR) and true clinical outcomes.
  • Does the trial answer the questions posed with high internal validity[4] and construct validity[5]?
  • Does the trial have statistical power[6] to answer research questions posed with high validity and confidence? Unsuccessful clinical trial does not have the statistical power to answer conclusively research questions.
  • High confidence in cause and effect relationship is essential for truthful communication with investors and validity of any assumptions made in the future based on the results of such trial.
  • Uncertainty of the meaning of data coming from clinical trials, its validity, accuracy, and confidence, which can be placed on each study, may be resolved through standardization of design of certain types of clinical studies through implementation of ISO standards. ISO standardization could reduce many uncertainties and increase probability of detection of reasonably foreseeable risks for individual therapeutic areas.
  • Incentives toward timely and complete publication of trial results (ClinicalTrials.gov).
  • Incentives to include NCT number in all publications as a clear identifier of data source.
  • Discouragement of multiple publication of the same trial in multiple different journals.
[1] Valdova V, Sheckler R, Abdulkhaleq A, Wagner S: The usability of Systems-Theoretic Accident Model and Processing (STAMP) in drug development (manuscript, 2015).
[2] Valdova V, Sheckler R: Risk Analysis Primer. http://www.aretezoe.com/#!risk-analysis-primer/c1h0v (Dec 2014)
[3] Ibid.
[4] Internal validity is the confidence that we can place in the cause and effect relationship in a study: "Could there be an alternative cause, or causes, that explain my observations and results?"
[5] Construct validity determines whether the program measured the intended attribute.
[6] The power of a statistical test is the probability that the test will reject the null hypothesis when the null hypothesis is false i.e. it will not make a Type II error, or a false negative decision. As the power increases, the chances of making a Type II error decrease. The probability of a Type II error is referred to as the false negative (β). Therefore power is equal to 1‐β, which is also known as the sensitivity.