Abstract

Dear CAT Committee Members,

The International Stem Cell Society (STEMSO) welcomes and appreciates the opportunity to submit comments on the European Medicine Agency’s (EMA’s) Reflection Paper on Classification of Advanced Therapy Medicinal Products (ATMPs). http://bit.ly/1rn84cA

STEMSO applauds the Committee for Advanced Therapies (CAT) for its efforts in regulating this area of medicine. STEMSO believes that regenerative medicine will be the future of medical practice and the pharmaceutical supply industry and fully understands the need for stringent regulations for the classification of cellular therapies as well as medical guidance by central governments for the purposes of maintaining safety and efficacy of medications and devices.

The International Stem Cell Society, STEMSO, is a non-profit organization representing a diverse membership from the regenerative medicine industry such as device manufacturers, physicians, health care facilities, researchers, attorneys, veterinarians, and patient advocates who have their own particular interests in cellular therapies and have joined together as an organization to respond to the EMA’s reflection paper. Non-member organizations and medical doctors have also contributed their input for this letter.

STEMSO submits the following comments and recommendations concerning the “Reflection Paper on the Classification of Advance Therapy Medicinal Products”.

General comments

STEMSO believes the proposed classification needs some revision in order to balance the best interests of patients and, at the same time, properly address the EMA’s concerns. Therefore, STEMSO believes that allogeneic cells or tissues for the purpose of mass production and distribution should be regulated as a drug. To strike a balance, some allowance for patients to use either their own cells or donated cells for an individual therapy for one time use should be allowed under the classification without classification as a drug. This balance is needed, as it is highly unlikely that any one individual patient or clinic could economically afford or wait for the full Investigational New Drug (IND) process to take place to treat one patient each time, regardless of safety or efficacy concerns.

There are many clinics and physicians around the world using autologous and allogeneic cellular therapies to treat several disease conditions and have produced overwhelming documentation showing safety and efficacy. Since these were individualized therapies for individual patients, the cell tissues were never intended to be mass-produced, distributed, or regulated as a drug.

Select, individualized cellular therapies have been employed safely and effectively for many years in clinical translation. Authors such as Hernigou describes his use of Bone Marrow Concentrate (BMC) to help bone and rotator cuff tear repair since the late 90s. These procedures have had an excellent safety record. As of 2013, the publicly posted clinical trial database at www.clinicaltrials.gov has shown 359 clinical trials using Mesenchymal Stem Cells (MSCs) with a very wide range of therapeutic applications worldwide. Bone marrow transplants have been utilized to treat blood borne cancers for over 50 years. It must be noted that since 1986, in-vitro fertilization has become commonplace throughout the world as a regenerative procedure that has been completed safely and effectively and involves, in some cases, substantial manipulation of cellular tissues and risk to expectant mothers.

1. STEMSO believes that by its very definition, Regenerative Medicine intends to use living cells in order to repair, replace, and regenerate missing, damaged, or degenerating tissue. The proposed classification of Advanced Therapy Medicinal Products by “Mode of Action” (MoA) criteria, which states:

“. . . administered to human beings with a view to regenerating,
repairing, or replacing a human tissue”

should be struck from the regulation as a classification criteria. (Section 2.2.1 lines 193-196)

2. STEMSO believes that a new, working definition of ATMPs should be created to:

a. Exempt both autologous and individualized allogeneic point of care cell therapies from the list of ATMPs. Specifically,

I. Bone marrow concentrate (BMC) used for purposes other than hematological use,

and

II. Stromal Vascular Fraction (SVF) derived from adipose tissue by enzymatic digestion.

b. Exempt situations when individualized, non-homologous, autologous or allogeneic cell therapy may be performed with signed, informed consent of the patient or delegated informed consent for compassionate care situations.

The scope of 2001/83/EC (Article 2) http://bit.ly/1uGJ2nN limits the regulation of cells and tissues in Europe as it defines the authority of regulated products when it states,” the provisions of this directive shall apply to industrially produced medicinal products for human use intended to be placed on the market in member states.” Since Regulation 1394/2007 http://bit.ly/1vbtWrR is an amendment to Directive 2001/83/EC, the provisions of 1394/2007 are guided by the scope of 2001/83/EC, by definition. Therefore, it is clear that cells and tissues that are ‘placed on the market’ are regulated and, the inverse applies if such cells or tissues are not placed on the market. The term ‘placed on the market’ is not defined in 2001/83/EC, however, the medical device directive 93/42/EC http://bit.ly/1vbvm5L provides a definition of ‘placed on the market’ that provides guidance on the intent of such a term/condition. Specifically, article 1(2)h of 93/42/EC defines placed on the market as: “ the first making available in the return for payment or free of charge…with a view to distribution and or use in the community market.” The 2014 EU ‘Blue Guide’ also adds clarity to the meaning of ‘placed on the market’ when it states, “placing on the market is considered not to take place were a product is….manufactured for one’s own use”. Furthermore, the European Commission report of 28 March 2014 on Regulation 1394/2007 has acknowledged the absence of regulatory authority over point-of-care autologous cells and tissues when it stated, “new innovative products, which are not clearly captured by existing provisions, are emerging…….its reinjection into the donor with the same procedure raises question as to how these treatments should be regulated”. The same report illustrates that Regulation 1394/2007 was not intended to apply to autologous point-of-care cells and tissues due to the practical realities of not being able to comply with the quality and GMP requirements of 1394/2007 when it stated, “requiring autologous products that are manufactured at the hospital prior to the administration to the patient to comply with the quality controls and manufacturing requirements of standardized chemical-based medicinal products would prevent the development of these treatments in practice as batch release certification would be required per treatment and a manufacturing license would be required per hospital”.

Therefore, it is abundantly clear that autologous cells and tissues produced in the same surgical procedure and at the point of care are not regulated in Europe due to the fact that they do not meet the minimal jurisdictional burden of being ‘placed on the market’, regardless of how the cells are used. We encourage the European Union to clarify the exemption of autologous same surgical procedure cells and tissues in much the same way as Directive 2004/23/EC (Article 2) and in a similar manner as the FDA’s exclusion of autologous same surgical procedure cells and tissues (HCT/P) in 21 CFR 1271.15(b). http://1.usa.gov/1Dxo1Cb

3. STEMSO brings to the Committee for Advanced Therapies (CAT’s) attention that historical data from clinical studies have not shown serious adverse reactions associated with autologous and allogeneic MSC therapy. ¹ For this reason, STEMSO believes that single, individualized therapies to treat one patient with autologous or allogeneic cells for homologous or non-homologous use should be allowed under the practice of medicine.

4. In order to accomplish the above referenced individualized “practice of medicine”, STEMSO requests that cell expansion with culture, enzymatic digestion of tissue, and differentiation/activation with growth factors be exempted from the list of substantial manipulations only for point of care, individualized therapies. (Section 2.2.3 lines 264-267).

Respectfully Submitted,

The International Stem Cell Society (STEMSO)
Douglas Hammond, President and Co-Founder

Kathy Hebert, CEO and Co-Founder
STEMSO
stemso.org