Raising the Barriers to Access to Medicines in the Developing World – The Relentless Push for Data Exclusivity

Since the adoption of the WTO‐TRIPS Agreement in 1994, there has been significant controversy over the impact of pharmaceutical patent protection on the access to medicines in the developing world. In addition to the market exclusivity provided by patents, the pharmaceutical industry has also sought to further extend their monopolies by advocating the need for additional ‘regulatory’ protection for new medicines, known as data exclusivity. Data exclusivity limits the use of clinical trial data that need to be submitted to the regulatory authorities before a new drug can enter the market. For a specified period, generic competitors cannot apply for regulatory approval for equivalent drugs relying on the originator's data. As a consequence, data exclusivity lengthens the monopoly for the original drug, impairing the availability of generic drugs. This article illustrates how the pharmaceutical industry has convinced the US and the EU to impose data exclusivity on their trade partners, many of them developing countries. The key arguments formulated by the pharmaceutical industry in favor of adopting data exclusivity and their underlying ethical assumptions are described in this article, analyzed, and found to be unconvincing. Contrary to industry's arguments, it is unlikely that data exclusivity will promote innovation, especially in developing countries. Moreover, the industry's appeal to a property rights claim over clinical test data and the idea that data exclusivity can prevent the generic competitors from ‘free‐riding’ encounters some important problems: Neither legitimize excluding all others.     

Antibiotic bill doesn't GAIN enough ground

With an eye to tackling the growing problem of antimicrobial drug resistance, uS lawmakers last month proposed new incentives to jump-start the ailing antibiotic industry. but the legislation as written is not likely to have the intended consequences, as it fails to adequately shield companies from competition with generic drugs. To truly entice investment and research from the drug industry, the bill needs to simplify the path to regulatory approval, provide greater protection from generic competition and aid drug companies with intellectual property extensions, tax relief and guaranteed market commitments.     

Clinical programs in the development of similar biotherapeutic products: rationale and general principles

Similar biotherapeutic products (SBPs) or biosimilars are biologics developed by pharmaceutical manufacturers to match originator biologics that have been on the market for a long time and lost their exclusivity (patent and market protection). The recently issued WHO guidelines on evaluation of SBPs provide clear guidance for manufacturers and regulators on how to develop and gain approval for these products. The present contribution illustrates the rationale for and general principles of the clinical programs used in the development of SBPs, taking the example of the three biosimilar products developed and marketed in Europe by Sandoz, namely growth hormone (Omnitrope?, the first ever EU biosimilar approval), erythropoietin α (Binocrit?), and filgrastim (Zarzio?).     

Trends in US approvals: new biopharmaceuticals and vaccines

The efficient development and approval of new therapeutics and vaccines is vital to the health and welfare of patients. Tufts Center for the Study of Drug Development has collected and analyzed data for new protein therapeutics and vaccines approved in the USA during the past decade. Our results suggest trends toward longer clinical and approval phases for the therapeutics, particularly for oncology products. In this Opinion article, we discuss various legislative acts and FDA initiatives that might improve the efficiency of drug development and approval. Furthermore, few new vaccines have been approved in the past 10 years owing, at least in part, to the lack of incentives for the development of the products. We predict that this might change in the future as government and industry respond to the twin threats of the global spread of infectious diseases and potential bioterrorism.     

The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA.

In October 2021, melphalan flufenamide (melflufen) was withdrawn from the US market for the treatment of multiple myeloma. The decision occurred based on results from a phase 3 randomized controlled trial (RCT) which showed numerically inferior overall survival, which previously led the FDA to halt all trials involving this drug. We highlight four issues raised by the approval fate of melflufen. First, the OCEAN trial was designed with a substandard control arm: negative results occurred despite this bias theoretically favoring the experimental arm. Second, a new compound, derived from a well-known drug, is not well fitting the accelerated pathway principles, unless being robustly tested against its parent drug. Third and four, allowing a new compound on the market, while there are known alternatives, and imminent confirmatory data, has the potential to harm patients while bringing earlier market share and profit to the company. While the FDA and the company should be commended for pushing a potentially dangerous product off the US market despite recent approval, yet a re-evaluation of regulatory processes is needed to ensure that cancer patients have timely access to effective medications while being protected against potentially detrimental ones.     

FDA regulation of invasive neural recording electrodes: a daunting task for medical innovators

The U.S. Food and Drug Administration (FDA) is charged with assuring the safety and effectiveness of medical devices. Before any medical device can be brought to market, it must comply with all federal regulations regarding FDA processes for clearance or approval. Navigating the FDA regulatory process may seem like a daunting task to the innovator of a novel medical device who has little experience with the FDA regulatory process or device commercialization. This review introduces the basics of the FDA regulatory premarket process, with a focus on issues relating to chronically implanted recording devices in the central or peripheral nervous system. Topics of device classification and regulatory pathways, the use of standards and guidance documents, and optimal time lines for interaction with the FDA are discussed. Additionally, this article summarizes the regulatory research on neural implant safety and reliability conducted by the FDA's Office of Science and Engineering Laboratories (OSEL) in collaboration with Defense Advanced Research Projects Agency (DARPA) Reliable Neural Technology (RE-NET) Program. For a more detailed explanation of the medical device regulatory process, please refer to several excellent reviews of the FDA's regulatory pathways for medical devices [1]-[4].     

The FDA and designing clinical trials for chronic cutaneous ulcers

Treatment of chronic wounds can present a challenge, with many patients remaining refractory to available advanced therapies. As such, there is a strong need for the development of new products. Unfortunately, despite this demand, few new wound-related drugs have been approved over the past decade. This is in part due to unsuccessful clinical trials and subsequent lack of Food and Drug Administration (FDA) approval. In this article, we discuss the FDA approval process, how it relates to chronic wound trials, common issues that arise, and how best to manage them. Additionally, problems encountered specific to diabetic foot ulcers (DFU) and venous leg ulcers (VLU) are addressed. Careful construction of a clinical trial is necessary in order to achieve the best possible efficacy outcomes and thereby, gain FDA approval. How to design an optimal trial is outlined.     

Worldwide experience with biosimilar development

Limited access for high-quality biologics due to cost of treatment constitutes an unmet medical need in the US and other regions of the world. The term “biosimilar” is used to designate a follow-on biologic that meets extremely high standards for comparability or similarity to the originator biologic drug that is approved for use in the same indications. Use of biosimilar products has already decreased the cost of treatment in many regions of the world and now a regulatory pathway for approval of these products has been established in the US. The Food and Drug Administration (FDA) led the world with the regulatory concept of comparability and the European Medicines Agency (EMA) was the first to apply this to biosimilars. Patents on the more complex biologics, especially monoclonal antibodies, are now beginning to expire and biosimilar versions of these important medicines are in development. The new Biologics Price Competition and Innovation Act (BPCIA) allows the FDA to approve biosimilars and allows the FDA to lead on the formal designation of interchangeability of biosimilars with their reference products. The FDA''s approval of biosimilars is critical to facilitating patient access to high-quality biologic medicines and will allow society to afford the truly innovative molecules currently in the global biopharmaceutical industry''s pipeline.Key words: monoclonal antibodies (mAbs), biosimilars, recombinant biopharmaceuticals     

Probiotics: time for a dose of realism

There is already a long research and retail history of probiotics, but progress in the scientific and medical validation of these products has been extremely slow. Even now, adequate information by which the consumer and health professional can judge the efficacy and safety of retailed probiotics is lacking. Probiotic products have not been subjected to large scale trials of efficacy that are used in the pharmaceutical industry. Without these trials and subsequent approval by fastidious regulatory agencies such as the FDA (USA), probiotics continue to languish in the self-care health market. Optimistically, a new generation of probiotics may be developed that have medical validity with respect to the prevention or treatment of atopic and inflammatory bowel diseases. These new products, however, will need to be targeted at the alleviation of specific medical conditions, and the mechanistic basis of their effectiveness will need to be provided.     

Worldwide experience with biosimilar development

Limited access for high-quality biologics due to cost of treatment constitutes an unmet medical need in the United States (US) and other regions of the world. The term “biosimilar” is used to designate a follow-on biologic that meets extremely high standards for comparability or similarity to the originator biologic drug that is approved for use in the same indications. Use of biosimilar products has already decreased the cost of treatment in many regions of the world, and now a regulatory pathway for approval of these products has been established in the US. The Food and Drug Administration (FDA) led the world with the regulatory concept of comparability, and the European Medicines Agency (EMA) was the first to apply this to biosimilars. Patents on the more complex biologics, especially monoclonal antibodies, are now beginning to expire and biosimilar versions of these important medicines are in development. The new Biologics Price Competition and Innovation Act allows the FDA to approve biosimilars, but it also allows the FDA to lead on the formal designation of interchangeability of biosimilars with their reference products. The FDA’s approval of biosimilars is critical to facilitating patient access to high-quality biologic medicines, and will allow society to afford the truly innovative molecules currently in the global biopharmaceutical industry’s pipeline.     

Current state of U.S. Food and Drug Administration regulation for cellular and gene therapy products: potential cures on the horizon

Cellular & Gene Therapies (CGTs) are complex products, which have been key foci of the International Society for Cell & Gene Therapy (ISCT). For this ISCT North American Legal & Regulatory Affairs Committee review publication, CGTs include but are not limited to somatic cell-based therapies, pluripotent cell-derived cell-based therapies, gene- or non-gene-modified or gene edited versions of these cell-based therapies, in vivo gene therapies, organ/tissue engineered products, and relevant combination products. These products are regulated by the Food and Drug Administration (FDA) in the United States. This publication reviews selected laws, regulations, guidance, definitions, processes, types of meetings and submissions, and other key factors that the FDA follows and implements to regulate and support development of these types of products. These factors may be considered in order to help current and potential product developers/sponsors/applicants navigate through FDA regulatory pathways. We also review expedited programs including types of Designations available at the FDA, and their specific eligibility criteria. We include FDA and other stakeholder resources to consider regarding CGT regulation, to help prepare for CGT development and subsequent FDA approval.     

Proteomic cancer biomarkers from discovery to approval: it’s worth the effort

The current landscape of cancer biomarkers is changing rapidly, with new and exciting developments. With the advances of proteomic technologies, many potential cancer biomarkers have been discovered. However, the number of new cancer biomarkers cleared or approved by the US FDA is rather limited. Although technological advances are important, clearly defining intended use, good study design and appropriate patient specimens are critical for the success of FDA approval. While obtaining FDA clearance/approval for newly developed and clinically useful cancer biomarkers has been slow, the reward for patient care could be enormous.     

Sterile Products: Advances and Challenges in Formulation,Manufacturing and Regulatory Aspects—A Regulatory Review Perspective

For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided.     

Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges

Tremendous efforts have been made over the past few decades to discover novel cancer biomarkers for use in clinical practice. However, a striking discrepancy exists between the effort directed toward biomarker discovery and the number of markers that make it into clinical practice. One of the confounding issues in translating a novel discovery into clinical practice is that quite often the scientists working on biomarker discovery have limited knowledge of the analytical, diagnostic, and regulatory requirements for a clinical assay. This review provides an introduction to such considerations with the aim of generating more extensive discussion for study design, assay performance, and regulatory approval in the process of translating new proteomic biomarkers from discovery into cancer diagnostics. We first describe the analytical requirements for a robust clinical biomarker assay, including concepts of precision, trueness, specificity and analytical interference, and carryover. We next introduce the clinical considerations of diagnostic accuracy, receiver operating characteristic analysis, positive and negative predictive values, and clinical utility. We finish the review by describing components of the FDA approval process for protein-based biomarkers, including classification of biomarker assays as medical devices, analytical and clinical performance requirements, and the approval process workflow. While we recognize that the road from biomarker discovery, validation, and regulatory approval to the translation into the clinical setting could be long and difficult, the reward for patients, clinicians and scientists could be rather significant.     

Structure, membrane orientation, mechanism, and function of pexiganan — A highly potent antimicrobial peptide designed from magainin

The growing problem of bacterial resistance to conventional antibiotic compounds and the need for new antibiotics have stimulated interest in the development of antimicrobial peptides (AMPs) as human therapeutics. Development of topically applied agents, such as pexiganan (also known as MSI-78, an analog of the naturally occurring magainin2, extracted from the skin of the African frog Xenopus laevis) has been the focus of pharmaceutical development largely because of the relative safety of topical therapy and the uncertainty surrounding the long-term toxicology of any new class of drug administered systemically. The main hurdle that has hindered the development of antimicrobial peptides is that many of the naturally occurring peptides (such as magainin), although active in vitro, are effective in animal models of infection only at very high doses, often close to the toxic doses of the peptide, reflecting an unacceptable margin of safety. Though MSI-78 did not pass the FDA approval, it is still the best-studied AMP to date for therapeutic purposes. Biophysical studies have shown that this peptide is unstructured in solution, forms an antiparallel dimer of amphipathic helices upon binding to the membrane, and disrupts membrane via toroidal-type pore formation. This article covers functional, biophysical, biochemical and structural studies on pexiganan.     

Extending the market exclusivity of therapeutic antibodies through dosage patents

Dosage patents are one way to extend the market exclusivity of an approved drug beyond the lifetime of the patent that protects the drug as such. Dosage patents may help to compensate the applicant for the long period where the active pharmaceutical ingredient as such is already under patent prosecution, but not on the market yet, due to lengthy development and approval procedures. This situation erodes part of the time the drug is marketed under patent protection. Dosage patents filed at a later date can provide remedy for this problem. Examples of successful and unsuccesful attempts, and the reasons for the respective outcomes, are provided in this article.     

Potential of plants to produce recombinant protein products

Plants have great potential as photosynthetic factories to produce pharmaceutically important and commercially valuable biomedicines and industrial proteins at low cost. The U.S. Food and Drug Administration (U.S. FDA) has approved the drug Elelyso (taliglucerase alfa) produced by carrot cells for treatment of type 1 Gaucher’s disease in 2012. The commercial potential of biomedicines produced by molecular farming has dramatically improved due to the success of an experimental drug called ZMapp, which has immunological activity in Ebola patients. A cocktail of three monoclonal antibodies was produced in tobacco (Nicotiana benthamiana) plants (Chen and Davis 2016). At present, very few drugs made by this technology have been approved by worldwide authorities such as the U.S. FDA. However, plants have been proposed as a novel paradigm for commercial production of proteins over the next decade. In recent years, leading researchers on molecular farming have given more priority to the area of animal-free therapeutic proteins such as parenteral and oral vaccines. Although plant-based platforms have considerable advantages over traditional systems such as bacterial and animal systems, there are several obstacles to commercial-scale production, especially with regards to improving the quality and quantity of plant-produced biologics and industrial materials. One of the biggest barriers to commercialization of this technology is the intense scrutiny of these new plant varieties by regulatory agencies and the public as well as the high costs associated with their regulatory approval.     

预测：2016年FDA即将批准新药概述

2015 年全年美国 FDA 共批准 45 个新分子实体和新生物制品,本文列出了 2016 年可能获 FDA 批准的新药目录,并对具体批准日 期进行了预测。     

A recombinase-mediated system for elimination of antibiotic resistance gene markers from genetically engineered Bacillus thuringiensis strains.

A TnpI-mediated site-specific recombination system to construct genetically modified Bacillus thuringiensis strains was developed. Recombinant B. thuringiensis strains from which antibiotic resistance genes can be selectively eliminated were obtained in vivo with a new vector based on the specific resolution site of transposon Tn4430. For example, a cryIC gene, whose product is active against Spodoptera littoralis, was introduced into B. thuringiensis Kto harboring a cryIA(c) gene active against Ostrinia nubilalis. The resulting strain had a broader activity spectrum than that of the parental strain. It contained only B. thuringiensis DNA and was free of antibiotic resistance genes. This should facilitate regulatory approval for its development as a commercial biopesticide.     

Biosimilars: navigating the regulatory maze across two worlds

The impending loss of market exclusivity for established biologic products creates a lucrative market opportunity for biosimilars. However, complex and variable regulatory requirements between regions present challenges to developers. Understanding the regulatory differences between two major markets, Europe and China, will expedite entry into these key markets.