Tozinameran (BNT162b2) Vaccine: The Journey from Preclinical Research to Clinical Trials and Authorization.

Vaccination development and production was an essential question for the prevention and global control of COVID-19. The strong support from governing authorities such as Operation Warp Speed and robust funding has led to the development and authorization of the tozinameran (BNT162b2) vaccine. The BNT162b2 vaccine is a lipid nanoparticle-encapsulated mRNA that encodes for SARS-CoV-2 spike protein, the main site for neutralizing antibodies. Once it binds with the host cells, the lipid nanoparticles enable the transfer of the RNA, causing S antigens' expression of the SARS-CoV-2, conferring immunity. The vaccine is administered as a 2-dose regime 21 days apart for individuals 16 years and older. Pfizer-BioNTech's BNT162b2 vaccine was the first candidate to receive FDA-Emergency Use Authorization (EUA) on December 11, 2020. During phase 2/3 clinical trials, 95% efficacy was reported among 37,706 participants over the age of 16 who received the BNT162b2 vaccination; additionally, 52% efficacy was noted 12 days following the administration of the first dose of BNT162b2, reflecting early protection of COVID-19. The BNT162b2 vaccine has exhibited 100% efficacy in clinical trials of adolescents between the ages of 12 and 15. Clinical trials in pregnant women and children under the age of 12 are expected to also exhibit promising results. This review article encompasses tozinameran (BNT162b2) vaccine journey, summarizing the BNT162b1 and BNT162b2 vaccines from preclinical studies, clinical trial phases, dosages, immune response, adverse effects, and FDA-EUA.

Challenges of developing and conducting clinical trials in rare disorders.

Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N-of 1) need to be considered. The affected patients can be hard to identify, especially early in the course of their disease, are generally geographically dispersed, and are often children. Trials are frequently conducted on an international scale and may be subject to complex or multiple regulatory agency oversights and may be affected by local customs, cultures, and practices. A basic understanding of the FDA programs supporting development of drugs for rare diseases is provided by this review and the role of early consultation with the FDA is emphasized. Of recent FDA New Molecular Entities (NME) approvals, 41% (17 approvals) in 2014, 47% (21 approvals) in 2015, and 41% (9 approvals) in 2016 were for rare disease indications. Through effective interactions and collaborations with physicians, institutions, and patient groups, sponsors have been successful in bringing new treatments to market for individuals affected by rare diseases. Challenges to drug development have been overcome through the focused efforts of patients/families, non-profit patient advocacy groups, drug developers, and regulatory authorities.

Complementary medicine products: interpreting the evidence base.

Many patients use complementary medicine (CM) products, such as vitamins, minerals and herbs as part of self-care without professional advice or disclosure to their doctors. While use of CM products is gaining awareness by the medical community and there is mounting evidence for their safety, efficacy and cost-effectiveness, there is also the potential for adverse events from inappropriate use and/or withdrawal, as well as interactions with other medicines. Due to the unique and complex properties of many CM products, research evidence is specific to individual preparations and this can lead to confusion when assessing label claims and interpreting the results of clinical trials and systematic reviews. While the Australian regulatory environment for CM products is the same as for prescription medicines and is based on risk, there is a great need for consumers and clinicians to have access to easily understood, evidence-based information to facilitate informed decision-making.

Clinical Trials, Data Protection and Patient Empowerment in the Era of the New EU Regulations.

Cancer clinical trials and, in general, cancer clinical research by definition need a multi-modality approach. It is not enough to discover and register new drugs. To get cancer under control requires us to perform complex clinical studies that integrate drugs, companion diagnostics, new or improved surgical procedures and new radiotherapy approaches as well as, most importantly, to integrate all available information. This includes biological material and, of increasing importance, large amounts of data using big data technologies. To personalise treatment, genetic data are more and more frequently used. Therefore, the general approach is holistic. Legislators, on the other hand, work in a silo mentality; the needs of clinical research are poorly understood, and legislation focuses on either health care or the commercialisation of a product, and not on clinical research. In the last 2 years the EU has drafted several major regulations touching on clinical trials, in vitro diagnostics, medical devices and data protection, all of which will impact clinical research, although the silo mentality makes the overall framework inconsistent and potentially highly damaging to the EU's capacity to make rapid progress in the field of personalised medicine.

[Analysis and discussion on current condition of acupuncture clinical research registration].

To introduce the international registration condition of acupuncture clinical research. With the examples of World Health Organization International Clinical Trials Registry Platform and the U. S. National Institutes of Health Clinical Registration Platform, the registration method and current condition of acupuncture clinical trials in international clinical trials registration platform were analyzed. The results indicate that the number of acupuncture clinical trials registration is gradually increased and the registration number from China is on the rise as well. But most domestic acupuncture clinical researches haven't been registered arid the researchers' valuing degree for clinical trials registration and methodology research needs to be improved.

Regulatory acceptance of animal models of disease to support clinical trials of medicines and advanced therapy medicinal products.

The utility of animal models of disease for assessing the safety of novel therapeutic modalities has become an increasingly important topic of discussion as research and development efforts focus on improving the predictive value of animal studies to support accelerated clinical development. Medicines are approved for marketing based upon a determination that their benefits outweigh foreseeable risks in specific indications, specific populations, and at specific dosages and regimens. No medicine is 100% safe. A medicine is less safe if the actual risks are greater than the predicted risks. The purpose of preclinical safety assessment is to understand the potential risks to aid clinical decision-making. Ideally preclinical studies should identify potential adverse effects and design clinical studies that will minimize their occurrence. Most regulatory documents delineate the utilization of conventional "normal" animal species to evaluate the safety risk of new medicines (i.e., new chemical entities and new biological entities). Animal models of human disease are commonly utilized to gain insight into the pathogenesis of disease and to evaluate efficacy but less frequently utilized in preclinical safety assessment. An understanding of the limitations of the animal disease models together with a better understanding of the disease and how toxicity may be impacted by the disease condition should allow for a better prediction of risk in the intended patient population. Importantly, regulatory authorities are becoming more willing to accept and even recommend data from experimental animal disease models that combine efficacy and safety to support clinical development.

Novel approaches are needed to develop tomorrow's antibacterial therapies.

Society faces a crisis of rising antibiotic resistance even as the pipeline of new antibiotics has been drying up. Antibiotics are a public trust; every individual's use of antibiotics affects their efficacy for everyone else. As such, responses to the antibiotic crisis must take a societal perspective. The market failure of antibiotics is due to a combination of scientific challenges to discovering and developing new antibiotics, unfavorable economics, and a hostile regulatory environment. Scientific solutions include changing the way we screen for new antibiotics. More transformationally, developing new treatments that seek to disarm pathogens without killing them, or that modulate the host inflammatory response to infection, will reduce selective pressure and hence minimize resistance emergence. Economic transformation will require new business models to support antibiotic development. Finally, regulatory reform is needed so that clinical development programs are feasible, rigorous, and clinically relevant. Pulmonary and critical care specialists can have tremendous impact on the continued availability of effective antibiotics. Encouraging use of molecular diagnostic tests to allow pathogen-targeted, narrow-spectrum antibiotic therapy, using short rather than unnecessarily long course therapy, reducing inappropriate antibiotic use for probable viral infections, and reducing infection rates will help preserve the antibiotics we have for future generations.

Who are the PDCO?

In January 2007, the Paediatric Regulation entered into force and established the Paediatric Committee (PDCO) within the European Medicines Agency. The goal of the PDCO is to improve the health of the children of Europe by increasing high-quality research for medicinal products and promoting the development and authorization of such medicines at the EU level. A major function of the PDCO is to formulate and authorize Paediatric Investigation Plans and Paediatric Use Marketing Authorisations. The EU's Seventh Framework Programme for Research has facilitated the establishment of consortia whose ultimate goal is to answer important clinical questions involving medicines commonly used "off-label", in children. The benefits of these consortia include enhanced collaboration amongst paediatricians, scientists and small to medium enterprises whose ultimate goal is to obtain an authorization for a new indication or formulation for use in the paediatric population. It will be interesting in a number of years time to measure the success of this very important European initiative.

[The difference in acknowledging the AAHRPP between China and America].

With the active encouragement of the Chinese government, all domestic clinical research institutes pay more attention to the human research protect program (HRPP) during the process of clinical trials, and actively follow the regulations of medical ethical practice. We could make fully preparation for the accreditation by the correlated international organizations only by further analyzing the Association for Accreditation of Human Research Protection Program (AAHRPP) from a whole and in each accreditation field at different levels, thus having a clear understanding the difference in acknowledging the difference between China's hospitals and America's hospitals.

FDA oversight of cell therapy clinical trials.

The U.S. Food and Drug Administration applies regulatory flexibility to balance benefits and risks to subjects in cell-therapy clinical trials.

Comparative effectiveness research: does the emperor have clothes?

With the recent allocation ofa $1.1 billion "down payment" to fund comparative effectiveness research (CER) from the American Recovery and Reinvestment Act of 2009 (generally referred to as the stimulus package) and with $300 million being allocated for the Agency for Healthcare Research and Quality (AHRQ), $400 million for the National Institutes of Health, and $400 million for allocation at the discretion of the Secretary of Health and Human Services and with the National Center for Complementary Alternative Medicine putting out a request for research proposals for Comparative Effectiveness Studies of Complementary and Alternative Medicine, it is safe to say CER has entered a new era. CER solves two historical concerns for complementary and alternative medicine (CAM) researchers; first it focuses on effectiveness not efficacy; second it tests holistic approaches to care. Because it allows the providers to give care in any way they choose, it avoids the problem of reductionism inherent in standard random controlled trials. In CER, the provider can continue to practice holistically and to use individualized medicine to treat the patient. However, amid the largely positive responses to this move among researches in CAM, a more critical evaluation might be in order. This article argues that while the move to effectiveness research is a positive move for CAM, CER as currently being talked about and funded may just be a new form of privileging certain forms of evidence at the expense of other equally important and perhaps more relevant evidence.

Regulation of research: is it a drug trial or a supplement trial?

Investigators and sponsors of dietary supplement research need to know the relevant regulatory requirements and how to comply with them. This brief review describes how research on dietary supplements is regulated by FDA. In general, whether an FDA sanctioned Investigational New Drug (IND) application is required for a human research project on dietary supplement depends on the intended use and clinical setting of the clinical study, and not on the supplement's physical or chemical properties. Even if the study product is already available on the market as a dietary supplement, an IND will be required for products that will be used as a drug to treat, mitigate or prevent a disease or its related conditions in the proposed clinical study. On the other hand, for studies on structure and function endpoints, and not on drug use, no IND will be required. The paper also discusses the principles FDA uses to determine whether an IND is needed for clinical studies of surrogate endpoints that do not lead to approvable drug claims. Useful FDA contact information is also provided.