Submission of comments on ‘Reflection Paper on Classification of Advanced Therapy Medicinal Products.’ (EMA/CAT/600280/2010 Rev.1)

Submission of comments on ‘Reflection Paper on Classification of Advanced Therapy Medicinal Products.’ (EMA/CAT/600280/2010 Rev.1)

Per definition, “Advanced Therapy Medicinal Products (ATMP)” are classifying stem cells as drugs in Europe by EMA, provided they are more than minimal manipulated and having a specific medical claim.

EMA has asked interested stakeholder to submit comments which may potentially be incorporated in the next issue of ATMP regulation.

After consulting various stem cell patient organisations as well as clinics providing stem cell treatment we have submitted our recommendations regarding stem cell regulation in the frame of “Practice of Medicine”.

We fully accept that allogeneic stem cells and treatment with those cells constitute various health concerns from immunoreaction to teratomas and therefore need to follow the route of clinical trials before released to the market.

On the other hand, minimal manipulated allogeneic stem cell treatments performed in a day-clinic has to be seen differently as they do not expose a patient to safety risks others than normal medical treatment during an operation.

Consequently in many countries, minimal manipulated autologous stem cells and related treatments performed by a qualified physician with IRB approved protocols in a same day medical procedure have started to evolve and show impressive results.

As however the regulations of stem cells in most countries do not distinguish well between stem cells as drugs, like allogeneic stem cells more than minimal manipulated and autologous stem cells minimal manipulated there are conflicting interpretations possible when it comes to use of one or the other stem cell type.

We have, therefore,  tried to define better, than in the present regulation,  the difference between a stem cell as a drug following the clinical trial route and autologous stem cells used in a medical procedure with IRB approved protocols by a medical doctor in our comments on the reflection paper  of EMA.

In this comments we also like to draw the attention to some inconsistency of present stem cell regulations, we as ARISTOLOFT with our cooperation partners Cell Surgical Network, USA have recognized and mentioned those in our comments to EMA. Those comments and recommendations had been also reviewed and endorsed by various Stem Cell Patient Organisations, with may thousands of members.

Our joint comments are based on the open letter by Dr. Mark Berman and Dr. Elliot Lander, founders of the Cell Surgical Network.

CELL SURGICAL NETWORK, INC.

A professional corporation

 MARK BERMAN, M.D., F.A.C.S.     ELLIOT LANDER, M.D., F.A.C.S.
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August 7, 2014

Cell Surgical Network – Position in Consideration of the European Medicines Agency in Response to “Reflection Paper on Classification of Advanced Therapy Medicinal Products.”

Dear Members of the CAT,

We understand the need to provide some type of regulation in the area of using biologics for therapeutic goals.  Clearly, no one wants to put the public at risk beyond generally acceptable limits that always exist even when employing the therapeutic use of approved drugs or devices.  We also realize that much of the regulations developed by a multitude of medical organizations have used the framework developed by the US FDA.

The US FDA was mandated to provide regulations about the production of Human Cells, Tissues, and Tissue-Based Products (HCT/Ps) for the expressed purpose to assure the prevention of the transmission of communicable disease.  This request by the US Congress (2005 – 21 CFR part 1271) serves as the sole purpose of the regulation.  Somehow, competing scientists and doctors that would like to take advantage for self-interested reasons have managed to obscure this important issue.

In order to have jurisdiction over HCT/Ps the FDA needed to define under what conditions your body parts could be considered drugs.  To that end, of course, much like the mandate in the current “Reflection Paper,” they established a set of guidelines that would exempt one from such oversight.  When there is a risk of disease transmission, particularly when manufactured under laboratory constraints, then the FDA has particular jurisdiction and it’s rather clear how they can implement their authority over such organizations.  Indeed, in the USA, the FDA has closed down a number of organizations that claimed production of autologous stem cells from bone marrow and fat.  In all cases, the FDA cited lack of GMP facility or overall lack of cleanliness in violation of 21 CFR part 1271.  In order to assert their jurisdiction, they needed to show that the process involved in producing the particular HCT/Ps fell under their jurisdiction (i.e. qualified as a drug).  Contrary to this the FDA has evaluated a number of organizations that provided same day cells (adipose or bone marrow derived) at the point of care even with collagenase (GMP grade) enzyme and took no action to stop these organizations.

While the FDA clearly has jurisdiction over laboratory procedures, other than assessing possible risk of disease transmission with HCT/Ps, they have never had any jurisdiction over surgical procedures.  There is not a single surgical procedure approved by the FDA.  In this context, there are several situations where physicians (e.g. Cytori, Tissue Genesis, Cell Surgical Network and similar organizations) perform a closed sterile surgical procedure without any laboratory requirements using all GMP products thus eliminating any risk of communicative disease.

In the “Reflection” paper, under section 2.1.2 it describes several categories that “shall not be considered as substantial manipulations : cutting, grinding shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation, concentration or purification, filtering lyophilization, freezing, cryopreservation and vitrification.” 

However, in section 2.2.3  the paper then gives examples of substantial manipulation.  In particular, it notes “enzymatic digestion of tissue to release cells.  This is most often done using fat tissue and the enzyme collagenase.  We assert that this is inconsistent with the already noted list of acceptable manipulations – namely “cell separation” and it is by far less manipulative than irradiation or even soaking in antibiotic solution.  Collagenase is already an FDA approved medication (e.g. Xiaflex for Peyronie’s or Dupetryn’s Contracture).  Collagenase only affects collagen material and does not even enter the cell membrane or alter its characteristics.

The problem with collagenase stems from its manufacturing which originally came from bovine based products that were only approved for laboratory use.  Such products run the risk of transmissible spongiform encephalopathies (TSEs) and thus could pose the risk of disease transmission.  Current FDA and GMP manufactured collagenases are free of any such disease transmission risk.  Indeed, Cytori provides a proprietary based collagenase to process their SVF cells and has not been shut down by the FDA.  Indeed, they currently have an approved Investigational Device Exemption (IDE) that could not be possible if their collagenase use was such a violation of minimal manipulation.  When the FDA Tissue Reference Group (TRG) responds negatively to someone suggesting the use of collagenase this is because they have no knowledge of the particular collagenase and do not want to take any risk for approval under such simple circumstances.  They can reference this as possibly more than minimal manipulation in order to assert their jurisdiction.

If medical grade collagenase were really an issue, then they would shut down CSN, Cytori and any other organization using collagenase in the USA.  This is not the case as there is no risk of disease transmission (e.g. CSN uses Roche GMP collagenase).  In South Korea e.g., the official policy of the KFDA is that the use of collagenase constitutes “minimal manipulation”.

On a purely argumentative point, how can anyone claim that collagenase, which only affects collagen and not a phospholipid membrane, is substantially manipulative compared to irradiation which can completely change cell characteristics and one’s DNA, or even antibiotics that can permeate a cell membrane?  This is simply self-serving and based upon false representation and mis-interpretation of the FDA’s motives in their TRG responses.

Further, as a surgical procedure doctors have authority to use any approved device or drug any way they see fit.  No drug or device manufacturer can possibly file for every possible claim that doctors or surgeons ultimately utilize.

 In passing, it should also be noted that while the FDA ruled that cell expansion fell into the category of more than minimal manipulation, the actual problem related to closure of a Colorado based US organization performing cell expansion was due to lack of GMP laboratory facilities and thus their inability to demonstrate prevention of disease transmission.  Only after the FDA closed them for failure to meet GMP criteria did this organization sue the FDA claiming the FDA had no jurisdiction over the practice of medicine.  The FDA prevailed by using their own regulations to show that this organization produced a “drug” by virtue of “more than minimal manipulation” and thus they maintained jurisdiction and won in court and even appellate court.

Indeed, this very organization that got sanctioned by the FDA bears the primary responsibility for obtaining the FDA TRG responses directed toward collagenase.  We assert that the FDA will not nor should not approve anyone asking for such blanket approval without knowing specifics about their process.  Such approval puts the FDA at risk.  On the opposite note, one should realize that while the FDA can’t approve this procedure, they also have no jurisdiction to disapprove it – at least not when done under a surgical environment.

On a further note, in keeping with the basic FDA guidelines you have also adapted the necessity to be “of homologous use.”  If this jurisdiction really existed over a surgical procedure, then your organization and the FDA as well, would have jurisdiction over a multitude of surgical procedures.  For example, we’ve been using fat grafts for years – these are usually processed through liposuction and a variety of filtration techniques and then while commonly used in areas where fat is missing (homologous) it is not infrequently used to repair a variety of defects where fat is not the homologous tissue (e.g. contour defects following muscle trauma, as a plumping graft for a variety of sphincter repairs or as a filler substance for breast tissue defects).  Coronary artery bypass is frequently done using vein grafts (not homologous).  A bladder can be reconstructed using ileum (not homologous).  Neither the FDA nor the EMA intends to police such surgical procedures.  Such techniques come under the auspices of the state or national medical boards to determine if there’s any reason to limit such procedures.  

While we appreciate the need to prevent unscrupulous practitioners from taking advantage of their patients, doctors, nonetheless, have the ability to safely perform a simple surgical procedure and provide SVF to patients on an investigational basis that may benefit from it.  Please note the attached bibliography of articles that indicate the multitude of products that have been differentiated from SVF (see Addendum).  If, as surgeons in multidisciplinary teams, we can deploy SVF to our patients in a properly monitored investigative format we can gain a wealth of empirical data that can support fine tuning and further research while potentially helping patients that currently have no further option for viable treatments.  Our empiric findings demonstrate that we can reverse severe arthritis, repair COPD, repair heart disease, often correct or improve neurological degenerative conditions and much more.  It’s simply a violation of the Hippocratic oath to deny such treatment to properly well-informed patients. 

Ironically, while we have seen criticism emanating from a variety of PhDs hard at work at developing a variety of stem cell lines, it’s ironic that the vast majority of the 261 strains of NIH approved stem cell lines being researched and commercialized in the USA have failed to meet FDA tissue screening guidelines and demonstrate sterility.  Clearly, these cell strains actually place patients at greater risk while the work we do under completely sterile conditions has been unjustly criticized by some in the basic science community in the USA and unjustly regulated outside of the USA. 

We would recommend that you consider the approach taken by CSN and several of our colleagues working with point of care delivery of SVF – namely, at the current time, until adequate numbers and research has been completed to claim otherwise, patients should be allowed to procure SVF deployment 

a) as part of investigational studies;

b) with proper acceptable informed consents consistent with experimental protocols as outlined by the US Office of Human Research Protections;

c) as part of approved IRB protocols not commensurate  with FDA approval (because they don’t approve surgical procedures); and if possible,

d) through transparent online data collection in cooperation with all international providers.

As such, CSN currently has an extensive online database documenting extraordinary safety and excellent efficacy data on over 1,000 of our patients. CSN is indeed willing to share and improve our database with our worldwide colleagues giving us all the unique opportunity to share and stratify the very data that will help the scientists refine and improve their research.  We know from our experience within our network that cooperation and sharing of data has helped us improve our outcomes and increase our understanding of real clinical situations.  In well over 1,000 cases adverse events have been limited to a few liposuction concerns (mostly post-operative discomfort) and no direct problems related to SVF deployment. 

It would be in the public’s best interest for the EMA to recognize these different avenues and not restrict doctors from progressing to help their patients to the extent that they currently can.   Further, we are willing to meet in person should you find it useful to have additional discussions that can reasonably help set up appropriate standards without negating the surgical process and our current abilities to ethically perform investigational deployment of autologous cells.

Sincerely,
Mark Berman, MD, FACS                       Elliot Lander, MD, FACS

This letter was reviewed, discussed and endorsed by various stem cell patient organisation as follows:

ENDORSEMENTS:

Ref: Submission of comments on ‘Reflection Paper on Classification of Advanced Therapy Medicinal Products.’ (EMA/CAT/600280/2010 Rev.1)

For Patients, it is very difficult to understand, when they suffer from illnesses which present medicine cannot really treat, and that they are, in some countries, not able to freely choose their treatment with a responsible physician / clinic with experimental autologous stem cell treatment. Their health condition is often worsened as they have to treat at least their symptoms by taking “approved medicine” resulting that they suffer from additional long-termed side effects of those medication.

This regulatory situation has increased stem cell tourism and unfortunately opened doors to unscrupulous practitioners in exotic places who are taking potentially advantage of “desperate patients” to improve their health condition, but provide nothing more than the famous snake oil treatments, often worsening the health of patients at ridiculous prices.  

In our extensive experience, documented by many member patients of our organisations and their experience in qualified internationally well-known stem cell treatment clinics and reviews of scientific papers and studies regarding autologous stem cell treatment, we are fully in accordance with those qualified clinics / physicians, helping patients in their most difficult period in life with experimental autologous stem cell treatment, having shown very often no or little side effects, but improved quality of life considerably.

We are not talking about allogeneic stem cell treatment and understand that allogeneic stem cells are more than minimal manipulated, which should be produced in GMP environments like a pharmaceutical drug to be effective and therefore should be considered as a new medical product, following the clinical trial route before applied to humans.

Autologous stem cell treatment derived from e.g. adipose tissues in form of SVF, or from peripheral blood however,  is a treatments with own cells from own blood, own fat or PRP accepted in many countries as a medical personalized treatment to improve various health conditions by qualified physicians.

The comments of CSN, therefore are very much appreciated and we herewith fully endorse this endeavours, and hope that EMA will adopt this ideas supporting qualified physicians in the frame of medical practise to use autologous stem cells as described in the paper of Dr. Mark Berman, and Dr. Elliot Lander, CSN to treat patients in their home countries, e.g. Europe reducing the potentially dangerous route of stem cell tourism.

Falk Heinrichsohn         Claire Hooper                    Barbara Hanson           Robbie Gordon
Managing Partner        Administrator                    Co-Founder                     Administrator
Aristoloft            Adult Stem Cell Advocates      Stem Cell Pioneers  Right to Try Legislation

Date: 11 August 2014 

The submission of comments to EMA is still open (Deadline for submission of comments is 31 Oct. 2014) and we kindly asked interested stakeholders either as a clinic or as an individual to comment on the safe use of autologous stem cell treatment in Europe and the US to avoid the potentially dangerous route of stem cell tourism in exotic places.

Details of the “Reflection Paper”, the submission format, etc, etc can be obtained from the below link:

 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/WC500169466.pdf
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