Definition and application of good manufacturing process-compliant production of CEA-specific chimeric antigen receptor expressing T-cells for phase I/II clinical trial

Adoptive cell therapy employing gene-modified T-cells expressing chimeric antigen receptors (CARs) has shown promising preclinical activity in a range of model systems and is now being tested in the clinical setting. The manufacture of CAR T-cells requires compliance with national and European regulations for the production of medicinal products. We established such a compliant process to produce T-cells armed with a first-generation CAR specific for carcinoembryonic antigen (CEA). CAR T-cells were successfully generated for 14 patients with advanced CEA⁺ malignancy. Of note, in the majority of patients, the defined procedure generated predominantly CD4⁺ CAR T-cells with the general T-cell population bearing an effector–memory phenotype and high in vitro effector function. Thus, improving the process to generate less-differentiated T-cells would be more desirable in the future for effective adoptive gene-modified T-cell therapy. However, these results confirm that CAR T-cells can be generated in a manner compliant with regulations governing medicinal products in the European Union.     

The challenges of regulating stem cell-based products

Appropriate regulation of stem cell-based products is essential to ensure public safety and trust while minimising unnecessary barriers to product development, but presents numerous challenges. Weaknesses of existing legal frameworks include variation between jurisdictions and poor fit between product categories and new technologies. The new European Regulation on advanced therapy medicinal products is an important attempt to provide a consolidated regulatory framework for novel products. Others can learn from issues encountered in its development, including definition of product categories, ethical concerns, and the application of regulations to small-scale production. Several aspects of the Regulation will be useful models, but some larger questions remain unresolved. As reform efforts move forward, harmonisation and sharing of expertise will be vital to effective regulation.     

Role of the blood service in cellular therapy

Cellular therapy is a novel form of medical or surgical treatment using cells in place of or in addition to traditional chemical drugs. The preparation of cellular products - called advanced therapy medicinal products - ATMP in Europe, requires compliance with good manufacturing practices (GMP). Based on long-term experience in blood component manufacturing, product traceability and hemovigilance, selected blood services may represent ideal settings for the development and experimental use of ATMP. International harmonization of the protocols and procedures for the preparation of ATMP is of paramount importance to facilitate the development of multicenter clinical trials with adequate sample size, which are urgently needed to determine the clinical efficacy of ATMP. This article describes European regulations on cellular therapy and summarizes the activities of the 'Franco Calori' Cell Factory, a GMP unit belonging to the department of regenerative medicine of a large public university hospital, which acquired a certification for the GMP production of ATMP in 2007 and developed nine experimental clinical protocols during 2003-2011.     

Next generation and biosimilar monoclonal antibodies: Essential considerations towards regulatory acceptance in Europe February 3–4, 2011, Freiburg,Germany

The Next Generation and Biosimilar Monoclonal Antibodies: Essential Considerations Towards Regulatory Acceptance in Europe workshop, organized by the European Centre of Regulatory Affairs Freiburg (EUCRAF), was held February 3–4, 2011 in Freiburg, Germany. The workshop attracted over 100 attendees from 15 countries, including regulators from 11 agencies, who interacted over the course of two days. The speakers presented their authoritative views on monoclonal antibodies (mAbs) as attractive targets for development, the experience to date with the regulatory process for biosimilar medicinal products, the European Medicines Agency draft guideline on biosimilar mAbs, as well as key elements in the development of mAbs. Participants engaged in many lively discussions, and much speculation on the nature of the quality, non-clinical and clinical requirements for authorization of biosimilar mAbs.Key words: biosimilar, monoclonal antibody, European Medicines Agency, medicinal product regulation     

Regulation of advanced therapy medicinal products in Europe and the role of academia

Background aimsAdvanced therapy medicinal products (ATMP) are gene therapy, somatic cell therapy or tissue-engineered products regulated under (EC) No. 1394/2007 to ensure their free movement within the European Union while guaranteeing the highest level of health protection for patients. Academic good manufacturing practice (GMP) centers are major contributors in the development of ATMPs and this study assessed the impact of regulations on them.MethodsEuropean academic and non-industrial facilities (n = 747) were contacted, and a representative sample of 50 replied to a detailed questionnaire. Experienced centres were further selected in every Member State (MS) for semi-structured interviews. Indicators of ATMP production and development success were statistically assessed, and opinions about directive implementation were documented.ResultsFacilities experienced in manufacturing cell therapy transplant products are the most successful in developing ATMPs. New centres lacking this background struggle to enter the field, and there remains a shortage of facilities in academia participating in translational research. This is compounded by heterogeneous implementation of the regulations across MS.ConclusionsGMP facilities successfully developing ATMPs are present in all MS. However, the implementation of regulations is heterogeneous between MS, with substantial differences in the definition of ATMPs and in the approved manufacturing environment. The cost of GMP compliance is underestimated by research funding bodies. This is detrimental to development of new ATMPs and commercialization of any that are successful in early clinical trials. Academic GMP practitioners should strengthen their political visibility and contribute to the development of functional and effective European Union legislation in this field.     

Regulation of herbal medicinal products in the EU: an up-to-date scientific review

A new European legislation on herbal medicinal products (HMPs) was developed, in order to harmonise the use of HMPs in the 28 member states of the European Union, according to Directive 2004/24/EC which amended the basic legislation laid down in Directive 2001/83/EC. The objective of this legislation was to ensure the future existence of such products and to consider particular characteristics during the assessment of their quality, efficacy and safety, having defined two categories for herbal medicines: (a) well-established use HMPs, which can be granted a marketing authorisation; and (b) traditional herbal medicinal products which can be granted a registration based on their long-standing safe and efficient use. The Committee on Herbal Medicinal Products was established at the European Medicines Agency in 2004, in order mainly to provide community monographs and list entries on herbal substances and preparations. 120 monographs have been published since then, which offer a scientific and regulatory standard for their safety and efficacy, during their use as medicinal products. The HMPs can be placed in the market after quality, efficacy, and safety have been assessed according to the provisions of the legislation (Directive 2004/24/EC and Directive 2001/83/EC), with adequate labeling information to patients and health care professionals, distinguishing them from other product categories containing herbs like: foods, food supplements, medical devices and cosmetics.     

Surgical maggots and the history of their medical use

Biosurgery or maggot therapy is a method of non-operative treatment of chronic skin and soft tissue wounds based on the medicinal properties of the so-called “surgical maggots.” Biosurgery became popular in the period between World Wars I and II and has recently aroused great interest in the US, the United Kingdom, and some continental European countries. The method is known as “maggot debridement therapy” in the US and as “biosurgery” in the United Kingdom.     

Worm therapy: for or against?

This article succinctly reviews the weight of evidence supporting worm therapy, and asks the question whether the evidence is sufficient to support the use of parasitic worms as investigational medicinal products.     

Could EU herbal monographs contribute to Malta’s treatment armamentarium?

Ten years have passed since Directive 2004/24/EC regulating herbal medicinal products across the EU were published. The directive created the Committee on Herbal Medicinal Products within the European Medicines Agency whose remit includes the creation and publishing of official EU monographs on herbal medicinal products. These monographs include the official uses of the products and their evidence for efficacy and safety. To this effect, we are interested in analysing the potential impact herbal product EU monographs could have on the therapeutic treatment options available for prescribers in Malta. Therefore our aim was two-fold. First, to rationalise the spread of indications of the herbal substances listed in the community herbal monograph inventory and subsequently determine if these herbal substances could potentially contribute to the treatment options available in our local scenario (Malta). 128 EU monographs were analysed resulting in a total of 230 indications which subsequently codified into 42 unique ATC codes. The Malta Medicines List contains 1456 unique ATC codes. Comparative analysis of the Malta Medicines List revealed that the 21 therapeutic areas had 4 or less pharmaceutically used substances (5th level ATC codes) registered and therefore in our opinion are areas with limited therapeutic choice. The following 4 therapeutic areas, A05 bile and liver therapy, A13 tonics, A15 appetite stimulants and D03 preparations for treatment of wounds and ulcers, could potentially benefit from the registration of herbal medicinal products according to the EU herbal monographs. If such registration is effected the aforementioned areas would no longer be considered limited because more than 4 therapeutic choices would be available to prescribers. This study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and confirms the notion that herbal products could potentially increase the treatment options available in areas where few medical products have been registered due to Malta's small market size.     

Therapeutic bacteriophages as a rescue treatment for drug-resistant infections – an in vivo studies overview

Bacteriophages, highly prevalent in all environments, have found their use in medicine as an alternative or complement to antibiotics. The therapeutic use of bacteriophages was particularly popular in the 1920s and 1930s, until the discovery and introduction of antibiotics. Due to the dynamic growth of antibiotic resistance among bacterial strains, numerous international institutions (such as the FDA) have declared the search for novel treatment modalities to be of the highest priority. To date, bacteriophage therapy has not been registered for general use in Western countries. The regulation of biological medicinal products (within medicinal product regulation) does not contain a specific documentation frame for bacteriophages (only for vaccines, blood derived products, etc.) which, as active substances, need to meet specific requirements. Recently, the FDA allowed bacteriophage therapy to be used in the United States, via the Emergency Investigational New Drug scheme; clinical trials to compare the safety and efficacy of bacteriophage therapy are also permitted. To date, several therapeutic products of this type have made it to phase I or II; some clinical programmes have also been completed. This article cites numerous animal model studies and registered clinical trials, showing the safety and effectiveness of bacteriophage therapy, including infections caused by bacterial strains resistant to antibiotic treatment.     

Implementing quality by design for biotech products: Are regulators on track?

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency's Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular.     

Implementing quality by design for biotech products: Are regulators on track?

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency''s Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular.     

The Medicine and Medicinal Plants of C. S. Rafinesque

This paper pursues the lead of Bart K. Holland in utilizing classic literature as a guide to the pharmacologic potentialities of natural products. Instead of focusing on European texts, however, American medicinal plants are examined through the work of the influential naturalist Constantine S. Rafinesque (1783-1840). Rafinesque is discussed with special attention to his activities as a medical botanist. In particular, the plant species monographed in the main section of hisMedical Flora of the United States (1828-1830) are studied for their historical and current use as medicinal agents. The results are tabulated and presented in a bar graph. The study concludes that Rafinesque was a progressive therapist whoseMedical Flora is a promising guide for phytopharmacuetical prospecting with North American plants.     

European regulatory framework and practices for veterinary Leptospira vaccine potency testing

In Europe, the legal basis for requirements for medicinal products is described in the European Pharmacopoeia (Ph. Eur.) In the European Union, the Ph. Eur. is supplemented by several guidelines issued by the European Medicines Agency. Immunological veterinary products must comply with the Ph. Eur. monograph on veterinary vaccines and the accompanying texts, as well as specific monographs. The Ph. Eur. includes monographs on canine leptospirosis and bovine leptospirosis vaccines (inactivated). Both monographs require that an immunogenicity test be performed once in the target species during the life of a vaccine. The hamster challenge test is applied for batch potency testing of canine vaccines. Alternatively, serological tests or suitable validated in vitro tests to determine the content of one or more antigenic components indicative of protection may be performed. Vaccines for use in cattle are tested in a serological test in guinea pigs. The acceptance criteria in alternative tests are set with reference to a batch of vaccine that has given satisfactory results in the immunogenicity test. At a January 2012 European workshop, the suitability of the hamster potency test was questioned and unanimous agreement was reached that moving toward complete in vitro testing is possible and should be promoted.     

Next generation and biosimilar monoclonal antibodies: Essential considerations towards regulatory acceptance in Europe; February 3-4, 2011; Freiburg,Germany

The “Next Generation and Biosimilar Monoclonal Antibodies: Essential Considerations Towards Regulatory Acceptance in Europe” workshop, organized by the European Centre of Regulatory Affairs Freiburg (EUCRAF), was held February 3-4, 2011 in Freiburg, Germany. The workshop attracted over 100 attendees from 15 countries, including regulators from 11 agencies, who interacted over the course of the two days. The speakers presented their authoritative views on monoclonal antibodies (mAbs) as attractive targets for development, the experience to date with the regulatory process for biosimilar medicinal products, the European Medicines Agency draft guideline on biosimilar mAbs, as well as key elements in the development of mAbs. Participants engaged in many lively discussions, and much speculation, on the nature of the quality, non-clinical and clinical requirements for authorization of biosimilar mAbs.     

Risk Associated with the Use of Selected Ingredients in Food Supplements

This review focuses on four new product categories of food supplements: pre-workout, fat burner/thermogenic, brain/cognitive booster, and hormone/testosterone booster. Many food supplements have been shown to be contaminated with unauthorized substances. In some cases, the ingredients in the new categories of dietary supplements were medicinal products or new synthetic compounds added without performing clinical trials. Some of the new ingredients in dietary supplements are plant materials that are registered in the pharmacopoeia as herbal medicines. In other cases, dietary supplements may contain plant materials that have no history of human use and are often used as materials to ‘camouflage’ stimulants. In the European Union, new ingredients of dietary supplements, according to European Food Safety Authority or unauthorized novel food. Furthermore, selected ingredients in dietary supplements may be prohibited in sports and are recognized as doping agents by World Anti-Doping Agency.