Regulatory initiatives for natural latex allergy: US perspectives

The US Food and Drug Administration (FDA) has regulatory authority over foods, human drugs, cosmetics, medical devices, radiological products, biologics, and veterinary products. Among these products, FDA believes that the use of medical devices, including medical gloves, condoms, catheters, and breathing bags, represents the greatest source of natural latex proteins to exposed individuals. A medical device is defined in the Federal Food Drug and Cosmetic Act (FFDCA) as an instrument, apparatus, implement, machine, etc., that is intended for use in the diagnosis or treatment of disease or is intended to affect the structure or any function of the body of a human or other animal, and that does not achieve any of its principal intended purposes through chemical action in the body. This article provides some brief, general background about FDA's medical device regulatory process and then addresses the issue of natural latex allergy. Finally we discuss the steps the Agency has taken to evaluate the magnitude and nature of the problem, and FDA's efforts to assist manufacturers, health professionals, and others in minimizing exposure and sensitization to natural latex proteins in medical devices.     

Natural rubber latex protein reduction with an emphasis on enzyme treatment

Natural rubber latex (NRL), derived from the Hevea brasiliensis tree, is a material used to manufacture products in health care, including medical gloves. Proteins are a naturally occurring component of NRL. These proteins, which can be present on the surface of NRL gloves, have been related to hypersensitivity reactions in some humans who come into contact with them. These same proteins also help to maintain the latex colloidal stability during collection and transport prior to manufacture. Consequently, when measures are taken to remove or degrade these proteins, other problems can be introduced, such as destabilization of the latex and changes in its coagulation properties. Practical methods are available to reduce the extractable antigenic protein content of NRL products. We describe here methods of reducing proteins in commercial-grade NRL and finished products. NRL gloves manufactured with adequate leaching can produce products with lower levels of extractable antigenic proteins. Emphasis is given here to enzyme treatment of NRL, as this process is very effective in reducing antigenic proteins in NRL. While this technology adds marginally to the production cost of standard grades of NRL, it is still quite cost-effective when compared with postwashing NRL products or the use of synthetic latex. Moreover, enzyme-treated NRL maintains the excellent physical properties and performance of NRL.     

Quantitation of latex allergens

Minimizing allergen concentration in latex goods to prevent sensitization to natural rubber latex (NRL) and thereby the development of clinical allergy is acknowledged as of mutual interest for rubber manufacturers and regulatory health authorities. However, measuring total protein, the principal currently available method, cannot be deemed a satisfactory regulatory measure to control allergen content. Specific methods based on human IgE-containing reagents, such as radioallergosorbent test (RAST) inhibition, have been available in certain laboratories for demonstrating NRL allergens in rubber products but the methods lack standardization. Currently, one commercial test has become available for measuring individual NRL allergens by capture ELISA-based assays using monoclonal antibodies and purified or recombinant allergens. Such methods are specific, they can be properly standardized, and they are of sufficient sensitivity and reproducibility. Results from medical gloves collected in two national market surveys in Finland in 1995 and 1999, respectively, show that Hev b 6.02 and Hev b 5, the two major allergens for NRL-allergic adults, are the most abundant allergens regularly detectable in high- and moderate-allergen gloves. In addition, Hev b 3 and Hev b 1, the two major allergens for children with spina bifida, are also commonly found. In general, when the sum of the four allergens exceeded 1 microg/g, most NRL-allergic patients showed positive skin prick test reactions against them. Using these new methods assessment of threshold levels that could in due course become guidelines for the rubber industry and regulatory health authorities is becoming possible. Eventually, this progress is expected to lead to a declining incidence of latex allergy.     

Natural rubber latex allergy in the occupational setting

Over the last decade, the prevalence of natural rubber latex (NRL) allergy has reached epidemic proportions among workers who use or who are exposed to powdered latex products. NRL-associated occupational asthma is confined largely to those exposed to powdered latex glove use or other latex aerosols. The most frequent presenting symptom of NRL allergy is contact urticaria; inhalation may cause symptoms of allergic rhinitis and asthma. Skin prick testing is the most accurate tool for diagnosis of NRL allergy. The cornerstone of management is cessation of exposure; substitution with non-NRL or nonpowdered NRL gloves results in predictable rapid disappearance of latex aeroallergen.     

Virus penetration of examination gloves

Examination gloves worn for protection from biohazards were sampled and evaluated for their ability to exclude virus particles. We found that thin gloves manufactured from polyethylene or polyvinyl chloride are ineffective barriers while gloves of thin latex are superior but not without failure. Polyethylene and polyvinyl chloride gloves had failure rates of 40% and 22%, respectively. Following exposure to the common disinfectant, 70% ethanol, these failure rates increased to 94% and 56% for polyethylene and polyvinyl chloride gloves, respectively. Latex, although permeable to ethanol, was penetrated by virus less than 1% of the time regardless of whether the latex had been pre-exposed to disinfectant or not. This study highlights the need for caution on the part of those who rely upon examination gloves for protection from infectious agents as well as the need for establishing more adequate standards and testing procedures for their manufacture.     

The biological safety of condom material can be determined using an in vitro cell culture system.

Latex products have long been recognized as a cause of latex protein allergy. The increased usage of latex gloves, with the consequent increased occurrence of latex allergies appears to have escalated with increasing awareness of the transmission of HIV-AIDS and other infections. The use of condoms as a means to prevent the transmission of STD's (sexually transmitted diseases) and HIV-AIDS has been widely promoted. Although extensive testing is done to evaluate the physical quality of condoms, no information is available regarding the biological safety of condoms. This study was undertaken to determine the effects of short-term exposure to physiological levels of condom surface material on cell viability (MTT assay) and cell growth (crystal violet assay). A direct contact cell culture testing method (FDA test method F813-83 used to evaluate the cytotoxic potential of medical materials and devices) was used. The modified test method was found to be a sensitive test system for the evaluation of the biological safety of condoms. This study reveals the importance of evaluating the biological safety of all condoms that are commercially available, because of the potential health risk that may be associated with prolonged use of certain types of condoms.     

Latex sensitivity in a macaque (Macaca mulatta)

BACKGROUND AND HISTORY: An adult Macaca mulatta was examined because of a history of multiple episodes of conjunctivitis and an acute, pruritic, dermatitic eruption that affected the axillary and inguinal regions, forearms, thorax, and neck. METHODS AND RESULTS: Results of corneal staining, examination of skin scrapings and feces, fungal culture, CBC, and a thyroid profile (thyroxine/triiodothyronine concentrations) were negative or normal, with the exception of eosinophilia (1,040/mm3). Examination of a punch biopsy specimen of the skin indicated chronic, nonsuppurative eosinophilic dermatitis. Skin patch testing against 25 contact allergens was negative for a delayed-type hypersensitivity reaction. Allergen-specific IgE testing, using six monkey chow additives, also yielded negative results, but testing against latex revealed a strong positive result (0.74 KU/L) consistent with a latex allergy. A skin prick test performed by use of a latex supernatant revealed significant inflammation at the latex site at 72 h and one week. Vinyl gloves were substituted for latex gloves, and that resulted in a marked decrease in erythema, pruritus, and lichenification with no flares of dermatitis for four years. Repeat skin biopsy fourteen weeks after the original biopsy revealed normal epidermis; however, mild chronic active nonsuppurative, perifolliculitis persisted. CONCLUSION: Latex can induce allergic dermatitis in nonhuman primates and should be included in the differen tial diagnosis for atopic dermatitis.     

Latex and vinyl nonsterile examination gloves: status report on laboratory evaluation of defects by physical and biological methods.

We have reported previously (H. R. Kotilainen, J. P. Brinker, J. L. Avato, and N. M. Gantz, Arch. Intern. Med. 149:2749-2753, 1989) that the quality of nonsterile examination gloves available for clinical use may be extremely variable. In view of the concern over human immunodeficiency virus and hepatitis B virus transmission to health care workers, the continuing variability of gloves available for use, and the need for a simple and safe test, we have evaluated 2,500 vinyl (five brands) and 2,000 latex (four brands) gloves by the 300-ml and the newly proposed 1,000-ml water tests and for permeability to herpes simplex virus type 1 and poliovirus type 1, respectively. While all 300-ml watertight gloves were unlikely to leak herpes simplex virus type 1 (1.3% vinyl; 0.5% latex), poliovirus was recovered much more frequently (8.9% vinyl, 6.1% latex). In all gloves that passed the 1,000-ml test, herpes simplex virus type 1 was not recovered. Poliovirus was recovered infrequently (1.4% vinyl, 1.5% latex). Preliminary analyses suggest that the 1,000-ml water test has significantly increased sensitivity over the 300-ml water test in the detection of small holes in both vinyl and latex gloves that may allow the passage of viral particles. Gloves that pass a 1,000-ml water challenge are unlikely to allow the passage of a small virus such as poliovirus. Given that human immunodeficiency virus, hepatitis B virus and herpes simplex virus type 1 are larger particles than poliovirus, gloves that pass the 1,000-ml water test theoretically could provide better protection.     

Latex and vinyl nonsterile examination gloves: status report on laboratory evaluation of defects by physical and biological methods

We have reported previously (H. R. Kotilainen, J. P. Brinker, J. L. Avato, and N. M. Gantz, Arch. Intern. Med. 149:2749-2753, 1989) that the quality of nonsterile examination gloves available for clinical use may be extremely variable. In view of the concern over human immunodeficiency virus and hepatitis B virus transmission to health care workers, the continuing variability of gloves available for use, and the need for a simple and safe test, we have evaluated 2,500 vinyl (five brands) and 2,000 latex (four brands) gloves by the 300-ml and the newly proposed 1,000-ml water tests and for permeability to herpes simplex virus type 1 and poliovirus type 1, respectively. While all 300-ml watertight gloves were unlikely to leak herpes simplex virus type 1 (1.3% vinyl; 0.5% latex), poliovirus was recovered much more frequently (8.9% vinyl, 6.1% latex). In all gloves that passed the 1,000-ml test, herpes simplex virus type 1 was not recovered. Poliovirus was recovered infrequently (1.4% vinyl, 1.5% latex). Preliminary analyses suggest that the 1,000-ml water test has significantly increased sensitivity over the 300-ml water test in the detection of small holes in both vinyl and latex gloves that may allow the passage of viral particles. Gloves that pass a 1,000-ml water challenge are unlikely to allow the passage of a small virus such as poliovirus. Given that human immunodeficiency virus, hepatitis B virus and herpes simplex virus type 1 are larger particles than poliovirus, gloves that pass the 1,000-ml water test theoretically could provide better protection.     

Murine models for natural rubber latex allergy assessment

Murine models provide a powerful tool in the investigation of latex allergy and the development of intervention strategies. The immune responses to protein allergens of mice and humans are similar but differences related to the roles of IgE and IgG must be recognized. Mice have been shown to mount a dose and time-dependent IgE response to latex proteins following topical, respiratory, and subcutaneous exposures. Methods are available to evaluate cutaneous and respiratory responses to latex challenge in sensitized animals. These models have been used to investigate the role of route of exposure on the development of latex allergy and to provide a means for investigating the contribution of individual proteins to adverse respiratory and dermal responses. These models provide a mechanism for the evaluation of new technologies aimed at reducing the allergenicity of latex products, and for testing for the potential for cross-reactivity to new allergens in previously sensitized individuals. Murine models may also provide a method for testing immunotherapy strategies prior to initiating human trials.     

European Federation of Organisations for Medical Physics (EFOMP) Policy Statement 12.1: Recommendations on Medical Physics Education and Training in Europe 2014

In 2010, EFOMP issued Policy Statement No. 12: “The present status of Medical Physics Education and Training in Europe. New perspectives and EFOMP recommendations” to be applied to education and training in Medical Physics within the context of the developments in the European Higher Education Area arising from the Bologna Declaration and with a view to facilitate the free movement of Medical Physics professionals within Europe. Concurrently, new recommendations regarding qualifications frameworks were published by the European Parliament and Council which introduced new terminology and a new qualifications framework – the European Qualifications Framework (EQF) for lifelong learning. In addition, a new European directive involving the medical use of ionizing radiations and set to replace previous directives in this area was in the process of development. This has now been realized as Council Directive 2013/59/Euratom of 5 December 2013 which has repealed directive 97/43/Euratom. In this regard, a new document was developed in the context of the EC financed project "European Guidelines on the Medical Physics Expert" and published as RP174. Among other items, these guidelines refer to the mission statement, key activities, qualification framework and curricula for the specialty areas of Medical Physics relating to radiological devices and protection from ionizing radiation. These developments have made necessary an update of PS12; this policy statement provides the necessary update.     

Glove powder reduction and alternative approaches

This article addresses the role of glove powder in facilitating allergic reactions to natural rubber latex (NRL) and to the chemical additives in synthetic and NRL gloves as well as its role in eliciting postsurgical complications. Various dusting powders have been used historically to prevent gloves from sticking to each other and to facilitate donning. All have manifested adverse consequences for health care professionals and patients. Manufacturing methods for powder reduction and elimination are presented. The recently developed ASTM methods for the quantitation of powder on powder-free and powdered gloves are reviewed along with the new ASTM maximum powder limits for all medical gloves. Caution must be exercised when methods of protein and powder reduction are implemented to minimize the possibility of creating other adverse consequences.     

Physicochemical and functional assessments demonstrating analytical similarity between rituximab biosimilar HLX01 and the MabThera®

Development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China’s Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, ef?cacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.     

Measurement of latex proteins and assessment of latex protein exposure

Reduction of protein levels in manufactured natural rubber latex products is important for preventing sensitization and adverse allergic reactions to latex. Because of the complex nature of latex extracts, accurate protein measurement is a challenge. Standard total protein assays were effective in reducing protein levels from what were once extremely high levels, but these assays are plagued with false-positive reactions and limited sensitivity. An ELISA for antigenic protein has been standardized and promises to provide more consistent measurement of the proteins with potential to cause adverse reactions. Antigenic proteins represent the total protein fraction with potential to be allergenic. Measuring antigenic protein in a consistent manner should help to further reduce the level of sensitizing protein and further reduce allergic reactions to latex-medical products.     

Allergenic proteins of natural rubber latex

As the living cytoplasm of laticiferous cells, Hevea brasiliensis latex is a rich blend of organic substances that include a mélange of proteins. A small number of these proteins have given rise to the problem of latex allergy. The salient characteristics of H. brasiliensis latex allergens that are recognized by the International Union of Immunological Societies (IUIS) are reviewed. These are the proteins associated with the rubber particles, the cytosolic C-serum proteins and the B-serum proteins that originate mainly from the lutoids. Procedures for the isolation and purification of latex allergens are discussed, from latex collection in the field to various preparative approaches adopted in the laboratory. As interest in recombinant latex allergens increases, there is a need to validate recombinant proteins to ascertain equivalence with their native counterparts when used in immunological studies, diagnostics, and immunotherapy.     

Outcome of occupational latex allergy--work ability and quality of life

Objective

The quality of life (QOL) and work ability of health care workers allergic to natural rubber latex (NRL) were assessed after implementation of regulations on powder-free NRL gloves in Germany.

Methods

196 HCW with reported NRL allergy answered a questionnaire (response rate 58%) containing the Work Ability Index (WAI), Mini Asthma Quality of Life Questionnaire (MiniAQLQ), and Dermatology Life Quality Index (DLQI).

Results

63.2% still had NRL-related symptoms during the last 6 month. However on a scale from 0 to 10, the intensity of NRL-related symptoms decreased from 8.5 before to 2.3 after implementation of regulations on powder-free NRL gloves. A higher number of subjects were able to avoid NRL in the private than in the work environment (85% vs. 61%). NRL-related symptoms decreased and WAI increased with successful avoidance of NRL at workplace (b = 0.23, p = 0.003). QOL was only little affected by NRL allergy (mean: MiniAQLQ = 6.0; DLQI = 4.1).

Conclusions

Although there was improvement after implementation of powder-free NRL gloves, there is still a considerable number of HCW with NRL-related symptoms. Further investigations on latex avoidance and the cause of persisiting allergic symptoms in HCW with NRL allergy are therefore needed.     

Measurement of airborne latex allergens

A method for the standardized sampling and quantification of aeroallergens was developed. It proved suitable for the analysis of allergen loads in a variety of medical settings. Several studies demonstrate that the use of powdered allergenic latex gloves leads to a significant aeroallergen load which is responsible for IgE-mediated rhinitis, bronchial asthma, and conjunctivitis in health care workers. Only nonpowdered latex gloves with low or no allergen content should therefore be used.     

La radiothérapie interne vectorisée par les analogues de la somatostatine,en pratique,en 2019

Somatostatin receptors are overexpressed in differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET). Radiolabeled somatostatin analogs have been used for a few decades for imaging and more recently for peptide receptor radionuclide therapy (PRRT) in a theranostic approach. Medical access to PRRT has long been limited to a few European specialized medical centers despite promising results in large cohorts of patients. NETTER-1, a phase 3 randomized trial, has demonstrated a drastic improvement of midgut NET patients progression-free survival in PRRT arm as compared to somatostatin analogs, leading to marketing authorizations in USA and Europe. PRRT clinical availability is growing in France, with around 20 medical centers offering this innovative treatment for GEP-NET patients care in 2019. PPRT success-story should lead to improvements of radionuclide therapy developments, which will reshape our medical specialty to a more “clinically” practice. This review aims to detail PRRT in clinical practice in France in 2019, with emphasize on treatment indications, planning and practical aspects. Radioprotection aspects and future optimization perspectives will also be discussed.     

Diagnostic kits in parasitology: which controls?

The development of new diagnostic tools particularly for some parasitic "neglected diseases", is slowed or even hindered by limited resources assigned for basic and applied research in public institution and private sector. Even if the time-line and costs needed for developing a new In Vitro Diagnostic (IVD) test are generally lower compared to vaccines or new drugs, industry is poorly engaged in investing resources due to the perception of limited markets. To accelerate the development of diagnostics for the world's most deadly diseases, the World Health Organization's (WHO) Special Programme for Research and Training in Tropical Diseases (TDR), the United Nations Development Programme, the World Bank and the Gates Foundation, last year launched a new initiative, FIND (Foundation for Innovative New Diagnostics, www.finddiagnostics.org). The aim is to "apply the latest biotechnology innovations to develop and validate affordable diagnostic tests for diseases of the developing world". Ideally, a new diagnostic test should be accurately evaluated prior to use in medical practice. The first step would be a pre-clinical evaluation, an analytic study to determine its laboratory performance. A crucial point in this phase is the calibration of reagents (antigens, antibodies, DNA probes, etc.) against a standard reference preparation. WHO, through the WHO International Laboratories for Biological Standards, "provides International Biological Reference Preparations which serve as reference sources of defined biological activity expressed in an internationally agreed unit" (www.who.int/biologicals/IBRP/index.htm). Standardization allows "comparison of biological measurements worldwide" and ensures the reliability of diagnostic procedures. These preparations are generally intended for use in the characterization of the activity of secondary reference preparations (regional, national or in-house working standards). Unfortunately, international reference standards for parasitic diseases are not available at present, except for Toxoplasma antibodies. The first international standard reagent for Anti-Toxoplasma Serum was established in 1968 and at present, an international standard reference serum, Anti-toxoplasma serum, human TOXM is available at the National Institute for Biological Standards and Control (NIBSC) in UK. Several collaborative, multicenter studies were carried out to assess the performance of different methods and commercial tests for the diagnosis of toxoplasmosis, by providing to participating laboratories a panel of well-defined sera to be tested. A four-phase process following well-accepted methodological standards for the development of diagnostics, analogous to those internationally accepted for drugs and vaccines was recently proposed. The pre-clinical evaluation, the analytic study to assess sensitivity, specificity, predictive values in laboratory (phase I), should be followed by a proof of principle study to distinguish diseased from healthy persons in easily accessible populations (phase II). The evaluation of test performance in populations of intended use (phase III), and finally the delineation of cost-effectiveness and societal impact of new tests in comparison with existing tools (phase IV) should complete the validation procedure. In this context, national regulatory agencies play a major role in pre-market approval and post-market surveillance of IVDs. The European Community in 1998 approved a directive (Directive 98/79/EC) which rules the marketing of IVD medical devices, in order to harmonise the performance levels and standards in European countries. But, among IVDs for parasitic diseases, only those to detect congenital toxoplasmosis are submitted to defined procedures to provide the verification of products before their placing on the market and the surveillance after their marketing by a notified body, which perform appropriate examinations, tests and inspections to production facilities to verify if the device meets the requirements of the directive. In U.S.A., the Food and Drug Administration (FDA), through the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), provides a comprehensive and regulatory activity for IVDs through pre-market evaluation and post-market surveillance. In developing countries, the scarcity of resources limits the procedures through which the national control authority can assure safety, quality and efficacy of products marketed, both imported and locally manufactured.