Development of a regulatory framework for cellular technologies: USA, EU, WHO

Most types of tissue and cell transplantation in the world are going through the initial stage of their formation. Thus, in the USA and the EU, the use of stem cells (with the exception of bone marrow progenitor cells) is limited only to the initial stages of clinical trials involving a small number of patients. In many countries of the world, with the participation of WHO, scientific and expert potential is being concentrated to regulate this kind of activity, regulatory legal acts are being created.

In the USA, the regulatory framework is the most developedIt should be noted that the domestic regulatory framework for cell and tissue transplantation is just beginning to take shape, whereas these approaches have long been developed abroad.

So, today the USA has, perhaps, the most developed regulatory framework for human cells, tissues, products based on cells and tissues (abbreviated HCT/P). In 1997, at the suggestion of the US Food and Drug Administration (FDA), a new regulatory approach was introduced with respect to HCT/P. It provides for the regulation of the circulation of some HCT/P in accordance with section 361 of the Public Health Service Act (PHS Act), while the remaining HCT/P are subject to the same requirements as for medicines, medical devices and/or biological products according to section 351 of the PHS Act.

The so-called 361 HCT/P, which do not require marketing authorization, include products that meet all of the following requirements (21 CFR 1271/10):

(1) HCT/P were subjected to minimal treatment;
(2) HCT/P are intended for homologous use (that is, they perform the same role in the recipient's body as in the donor);
(3) The HCT/P production process does not provide for the combination of these cells or tissues with other substances, with the exception of water, salt solutions, sterilizing or preserving agents, and there are no safety problems.

The manufacturer of such products must register with the FDA and submit to the office a list of all HCT/P produced. Such products include: amniotic membranes used without the addition of other cells; bone, cartilage tissue; cornea, fascia, ligaments, pericardium, peripheral blood cells or umbilical cord blood stem cells (for autologous use or use in blood relatives of the 1-2 degree of kinship); sclera, skin, tendons, vascular grafts, heart valves, dura mater, reproductive cells and tissues.

The FDA has published 3 final sets of rules implementing the relevant regulatory norms regarding (1) HCT/P registration; (2) determining the suitability of HCT/P donors; (3) Good Tissue Practice for HCT/P.

Center for Evaluation and Research of Biological Products (Center for Biologics Evaluation and Research – CBER) The FDA regulates the circulation of both 361 and 351 HCT/P, but does not deal with vascularized human organs such as kidneys, liver, heart, lungs, pancreas. The CBER is also charged with regulating xenotransplantation (the source of the transplant is not the human body).

What are the drugs for cell therapy? The first example is the successful introduction by Dr. Paul Niehans in 1930 of a suspension of parathyroid gland cells to a patient who had them damaged during thyroidectomy. The following types of cell therapy are widely used today (Viosin E., Mudge S., 2005):

• replacement of cartilage tissue of large joints with in vitro grown chondrocytes (Carticel®, Genzyme Corporation);
• replacement of skin defects with skin flaps produced by keratinocytes in vitro (Epicel®, "Genzyme Corporation");
• use of hematopoietic stem cells – bone marrow transplantation.

As other examples of cell therapy, the FDA calls implantation of cells that become a source of various biologically active substances in the body, such as enzymes, cytokines, clotting factors; infusion of activated lymphoid cells; implantation of pretreated hepatocytes, myoblasts, pancreatic islet cells. The introduction of cells into the body can be carried out by infusions, injections or surgical implantation; the materials used in this case (all types of bases, fibers, etc.) can be considered excipients, active substances or medical products. Since the latter can interact with cells, they should be considered part of the finished biological product at the preclinical research stage (Guidance for Human Somatic Cell Therapy and Gene Therapy, 1998).

The application for an investigational drug (Investigation New Drug – IND) must be in the same format and contain the same sections as the IND of any investigational biological drug. The main emphasis in the regulatory assessment of IND when deciding on the conduct of phase I clinical trials should be given to safety and only then to the validity of the use of the drug.

If the composition of the product was changed during the development process, it is necessary to compare the biological activity of the original and modified product and, if necessary, repeat preclinical studies. The same applies to the later stages of research: the company must prove the similarity of the modified version or repeat the research.

Another new direction is gene therapy. The FDA briefly defines it as the use of genetic material to treat, reduce the severity of symptoms or prevent diseases. None of the products for gene therapy has yet received marketing permission, but CBER, taking into account their high potential and equally significant risks, is working to reduce the latter. To this end, in November 2006, a guide for the industry "Clinical trials of gene therapy – observation of participants to identify delayed side effects" was released. The latter may be the result of persistent biological activity of genetic material or other components of the product. Factors that increase the likelihood of such an adverse effect on the cells of the body, with the development of side effects months and years after treatment, are the persistence of the viral vector, the integration of genetic material into the patient's genome, prolonged expression of transgenes and impaired expression of recipient genes.

The FDA also regulates xenotransplantation products, some of which may be a combination of biological drugs and medical devices, for example, xenogenic cells placed in a device through which extracorporeal hemoperfusion is performed.

Another type of cell therapy products is placental/umbilical cord blood. Americans began experimenting with human stem cells (hESC) in 1998, when a group of scientists led by Dr. James Thomson from the University of Wisconsin developed a technology for isolating and growing such cells. Moreover, the financing of hESC research from the state budget began only in August 2001, so they are still in the early stages (stemcells.nih.gov; clinicaltrials.gov). A separate guide for the industry (project) is devoted to applying for a marketing permit for such a biological drug (biologic license application – BLA), where it is noted that BLAS can be filed regarding a product that:

• has undergone minimal processing;
• designed to restore hematopoiesis in patients with malignant tumors of the hematopoietic system;
• intended for use by a recipient who is not related to a donor (if intended for autotransplantation or for relatives of the 1-2 degree of kinship, you do not need to submit an application - see above).

Other varieties of peripheral or placental blood stem cell preparations should be tested clinically, for which IND is supplied. So far, their use is limited to the early stages of clinical trials.

Harmonised standards are being created in the EU countriesThe regulatory status of drugs for cell and tissue therapy in the EU member states has varied until recently.

Only recently, on October 30, 2007, the Council of Europe approved the Regulation on medicines for advanced therapeutics (No. 3627/07 of 10/15/2007) supplementing Directive 2001/83 and EC Regulation No. 726/2004. The Regulation on drugs for advanced therapies (drugs for gene therapy, somatic cell therapy and tissue engineering products) is special (lex special) in relation to Directive 2001/83. It is noted that the effect of this directive does not apply to drugs that are not prepared routinely and are used in the country of manufacture under the sole responsibility of a healthcare professional, who thus offers the patient a treatment developed specifically for him.

Since the examination of such products requires specific knowledge, the European Medicines Agency (EMEA) plans to create a Committee on Advanced Therapies (Committee for Advanced Therapies). If the product is combined, that is, it includes a medical device, the examination of this part is carried out by the appropriate authority. Such drugs, it is noted in the manual, must comply with the same regulatory principles as biotechnological agents of other types. However, the requirements for quality, preclinical and clinical assessment may be special. Such preparations should be produced in accordance with GMP requirements, which can be adapted to their specific characteristics.

WHO experts on the characteristic features of cell and tissue transplantsTwo WHO reports – the first and second global consultations on regulatory requirements for human cells and tissues for transplantation (dated 2004 and 2006, respectively) – give a more general idea of the relevance and development of this area in different countries.

In the first of the above–mentioned documents, WHO defines cell and tissue transplants (hereinafter referred to as CTT) as a specific class of medical products of important therapeutic value in the frequent absence of analogues for the restoration of vital functions. In many countries, there is a shortage of relevant rules and regulations in this area, as well as a shortage of necessary CTT, for example, the cornea of the eye. Many CTTS, WHO reports, cross state borders, often without legal grounds.

The participants of the above-mentioned WHO consultations paid attention to the following issues:

• creation of specifications of the main necessary CTTS used worldwide, transferred from country to country and presented in commercial markets;
• development of a quality management system to monitor the process of selecting donors and tracking clinical results;
• international cooperation in collecting information on adverse events during transplantation;
• The experience of some developed countries in streamlining the activities of organizations working with CTT by inspecting and licensing them, as a result of which many of these institutions were closed due to limited resources; the rest were networked to effectively implement a quality control system and improve access to them for patients.

It is interesting to note from WHO documents about the differences between most medicines and CTT. The first are mass-produced, in large batches, with the control of raw materials, according to a well-planned and proven scheme, for the "mass" consumer and have a relatively short shelf life. The latter are single products, very labor-intensive in production, with limited ability to control the raw materials, constant changes in the production process and often a long shelf life. It was also interesting to learn that the delegates of the above-mentioned consultations, despite the existence of a global market for cord blood storage banks, removed this product from the original version of the list of essential CTT due to lack of evidence of its clinical benefit.

In the same WHO report for 2006 we read about the role of PIC/S (Pharmaceutical Inspection Cooperation Scheme – Pharmaceutical Inspection Cooperation System) in the standardization of approaches to the production of CTT. In October 2005, a meeting of a group of experts who, within the framework of PIC/S, deal with these issues took place. At the meeting with the participation of 56 representatives of 27 countries, problems related to the inspection of centers working with blood preparations and other transplants were discussed. As a result, it was concluded that the requirements for these centers are similar to GMP requirements for pharmaceutical production, but the centers working with blood products have specific features that should be taken into account. The experience of PIC/S member countries in this area is limited, and many are just beginning to inspect such centers or certain types of their activities. The need for specialized training for inspectors was recognized, and the relevant PIC/S working group began to develop guidelines. It was stressed that the harmonization of approaches to inspections is important because of the circulation of CTT between countries. It is also noted that CTT is often used as a source for obtaining preparations of gene and cell therapy and tissue engineering, which are subject to regulatory requirements applied to medicines. Such production must comply with all GMP requirements (WHO, 2006).

Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of the Weekly "PHARMACY"

17.12.2007