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FDA drug candidacy acceptance criteria and steps: problems and way forward
... Moreover, some minor differences between these requirements have been consistently revealed by different agencies around the world, since some products can be approved in one country and the same product cannot be released on another continent. As a classic example, dipyrone is permitted in some countries with unblocked consumption; however, the FDA in the U.S. and its counterparts in several countries prohibited its common use [123]. Furthermore, the time for approval differs between agencies around the entire world. ...
Nanotechnology and drug-release biomaterials have been thoroughly explored in the last few years aiming to develop specialized clinical treatments. However, it is rare to find biomaterials associated with drug delivery properties in the current dental market for application in oral bone- and periodontal-related procedures. The gap between basic scientific evidence and translation to a commercial product remains wide. Several challenges have been reported regarding the clinical translation of biomaterials with drug-delivery systems (BDDS) and nanofeatures. Therefore, processes for BDDS development, application in preclinical models, drug delivery doses, sterilization processes, storage protocols and approval requirements were explored in this review, associated with tentative solutions for these issues. The diversity of techniques and compounds/molecules applied to develop BDDS demands a case-by-case approach to manufacturing and validating a commercial biomaterial. Promising outcomes such as accelerated tissue healing and higher antibacterial response have been shown through basic and preclinical studies using BDDS and nano-engineered biomaterials; however, the adequate process for sterilization, storage, cost-effectiveness and possible cytotoxic effects remains unclear for multifunctional biomaterials incorporated with different chemical compounds; then BDDSs are rarely translated into products. The future benefits of BDDS and nano-engineered biomaterials have been reported suggesting personalized clinical treatment and a promising reduction in the use of systemic antibiotics. Finally, the launch of these specialized biomaterials with solid data and controlled traceability onto the market will generate strong specificity for healthcare treatments in dentistry.
... Due to the growing recognition of the medical importance of herbal medicines [9] and their affordability, the demand for herbal medicines is increasing [7]. Although herbal medicines are used since antiquity, there needs to be solid convincing evidence concerning their clinical safety and efficacy, thus the need for exploratory studies like this [10]. ...
Plants have been well-known to be an excellent source of potentially bioactive compounds. Even with this great importance, modernization and industrialization continually threaten our knowledge of using plants as traditional medicines. In this study, ethanol and ethyl acetate crude extracts of Musa textilis, Agathis philippinensis, and Cinnamomum mercadoi leaves were investigated for its phytochemical content and toxicological potentials. These plants have been known to be used by indigenous people of Mat-I, Claveria Philippines, for various ailments. Standard methods were utilized to determine the qualitative presence of different phytochemicals while Brine Shrimp Lethality Assay was used to evaluate toxicological potentials. From the results, A. philippinensis ethyl acetate extracts and C. mercadoi ethanol and ethyl acetate extracts are considered active or slightly toxic at prolong administration. Results of phytochemical screening revealed presence of alkaloids, flavonoids, amino acids, triterpenoids, steroids and terpenoids in A. philippinensis ethyl acetate extracts and C. mercadoi crude ethanol and crude ethyl acetate extracts. While A. philippinensis ethanol extracts is observed to contain flavonoids, amino acids, triterpenoids, steroids and terpenoids. M. textilis ethanol extracts is observed to contain flavonoids, amino acids and steroids, while results revealed the presence of flavonoids, triterpenoids, steroids and terpenoids in its ethyl acetate extracts. A. philippinensis ethyl acetate extracts and C. mercadoi ethanol and ethyl acetate extracts showed to be active and contain bioactive components that could be potential for further studies. Further studies are suggested to isolate and characterize these natural products for in-depth bioassay studies.
Aqueous herbal formulations against enteric diseases in Malawi are stored in different containers and for different durations, a practice whose implications to the stability of the antimicrobial potency, pH and phytochemical presence has not been explored in Malawi. Formulations from P. guajava leaves and roots, M. azadirachta leaves and C. frutescens roots were stored in clay pots and plastic bottles and checked for their stability in antibacterial potency against Escherichia coli using the disc method, its pH changes and phytochemical presence. Phytochemicals were present mostly from day 2, pH was storage duration-dependent. Antibacterial potency depended on storage duration and was not affected by container material. Maximum antibacterial activity was observed in P. guajava leaves formulation in plastic bottle at 62% that of Erythromycin. The study showed that aqueous formulations can be stored in either plastic containers or clay pots without adversely affecting their potency.
Natural product drugs, or botanical drugs, are drugs composed of natural substances which has constituent and efficacy. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards on approving drug sales varies by countries. And also, thorough standardization, scientification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as international exchange in botanical drug market continues, importance of plant resources was emphasized, thus countries' ownership on domestic natural resources became vital. Not only establishing systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to effectively procure natural resources. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support on basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development.
Post-marketing drug withdrawals can be associated with various events, ranging from safety issues such as reported deaths
or severe side-effects, to a multitude of non-safety problems including lack of efficacy, manufacturing, regulatory or business
issues. During the last century, the majority of drugs voluntarily withdrawn from the market or prohibited by regulatory agencies
was reported to be related to adverse drug reactions. Understanding the underlying mechanisms of toxicity is of utmost importance
for current and future drug discovery. Here, we present WITHDRAWN, a resource for withdrawn and discontinued drugs publicly
accessible at http://cheminfo.charite.de/withdrawn. Today, the database comprises 578 withdrawn or discontinued drugs, their structures, important physico-chemical properties,
protein targets and relevant signaling pathways. A special focus of the database lies on the drugs withdrawn due to adverse
reactions and toxic effects. For approximately one half of the drugs in the database, safety issues were identified as the
main reason for withdrawal. Withdrawal reasons were extracted from the literature and manually classified into toxicity types
representing adverse effects on different organs. A special feature of the database is the presence of multiple search options
which will allow systematic analyses of withdrawn drugs and their mechanisms of toxicity.
Objective To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs’ originally approved indications.
Design Systematic review.
Setting Publicly accessible data on supplemental indications approved by the US Food and Drug Administration from 2005 to 2014.
Main outcome measures Types of comparators (active, placebo, historical, none) and endpoints (clinical outcomes, clinical scales, surrogate) in the efficacy trials for these drugs’ supplemental and original indication approvals.
Results The cohort included 295 supplemental indications. Thirty per cent (41/136) of supplemental approvals for new indications were supported by efficacy trials with active comparators, compared with 51% (47/93) of modified use approvals and 11% (7/65) of approvals expanding the patient population (P<0.001), almost all of which related to pediatric patients (61/65; 94%). Trials using clinical outcome endpoints led to approval for 32% (44/137) of supplemental approvals for new indications, 30% (28/93) of modified indication approvals, and 22% (14/65) of expanded population approvals (P=0.29). Orphan drugs had supplemental approvals for 40 non-orphan indications, which were supported by similar proportions of trials using active comparators (28% (11/40) for non-orphan supplemental indications versus 24% (10/42) for original orphan indications; P=0.70) and clinical outcome endpoints (25% (10/40) versus 31% (13/42); P=0.55).
Conclusions Wide variations were seen in the evidence supporting approval of supplemental indications, with the fewest active comparators and clinical outcome endpoints used in trials leading to supplemental approvals that expanded the patient population.
After approval, many prescription medications that patients rely on subsequently receive new black-box warnings or are withdrawn from the market because of safety concerns. We examined whether the frequency of these safety problems has increased since 1992, when the Prescription Drug User Fee Act, legislation designed to accelerate the drug approval process at the Food and Drug Administration, was passed. We found that drugs approved after the act's passage were more likely to receive a new black-box warning or be withdrawn than drugs approved before its passage (26.7 per 100.0 drugs versus 21.2 per 100.0 drugs at up to sixteen years of follow-up). We could not establish causality, however. Our findings suggest the need for reforms to reduce patients' exposure to unsafe drugs, such as a statement or symbol in the labeling, medication guides for patients, and marketing materials indicating that a drug was approved only recently.
While biotechnological advances, genomics and high throughput screenings or combinatorial and asymmetric syntheses have opened new vistas in drug discovery, the industry is facing a serious innovation deficit. Critics suggest that "we have become high throughput in technology, yet have remained low throughput in thinking". Post marketing failures of blockbuster drugs have become major concerns of industries, leading to a significant shift in favor of single to multi targeted drugs and affording greater respect to traditional knowledge. Typical reductionist approach of modern science is being revisited over the background of systems biology and holistic approaches of traditional practices. Scientifically validated and technologically standardized botanical products may be explored on a fast track using innovative approaches like reverse pharmacology and systems biology, which are based on traditional medicine knowledge. Traditional medicine constitutes an evolutionary process as communities and individuals continue to discover practices transforming techniques. Many modern drugs have origin in ethnopharmacology and traditional medicine. Traditions are dynamic and not static entities of unchanging knowledge. Discovering reliable 'living tradition' remains a major challenge in traditional medicine. In many parts 'little traditions' of indigenous systems of medicine are disappearing, yet their role in bioprospecting medicines or poisons remains of pivotal importance. Indian Ayurvedic and traditional Chinese systems are living 'great traditions'. Ayurvedic knowledge and experiential database can provide new functional leads to reduce time, money and toxicity -the three main hurdles in the drug development. We begin the search based on Ayurvedic medicine research, clinical experiences, observations or available data on actual use in patients as a starting point. We use principles of systems biology where holistic yet rational analysis is done to address multiple therapeutic requirements. Since safety of the materials is already established from traditional use track record, we undertake pharmaceutical development, safety validation and pharmacodynamic studies in parallel to controlled clinical studies. Thus, drug discovery based on Ayurveda follows a 'Reverse Pharmacology' path from Clinics to Laboratories. Herein we describe such approaches with selected examples based on previous studies.
A 61-year-old man presents to the emergency room with left-sided epistaxis that has continued for 1 hour. He estimates having lost approximately 1/2 cup of blood and reports no history of nasal obstruction, epistaxis, trauma, bleeding diathesis, or easy bruising. He has a history of hypertension. Medications include atenolol and baby aspirin. How should this patient be evaluated and treated?
Spontaneous reporting systems like MEDWATCH can be effective in revealing unusual or rare adverse events that occur with the use of medications, and such reports may often be sufficient to assign causality. However, spontaneous reports do not reliably detect adverse drug reactions (ADRs) that occur widely separated in time from the original use of the drug or that represent an increased risk of an adverse event that occurs commonly in populations not exposed to the drug. In these situations, spontaneous reports alone do not provide sufficient evidence to conclude that the adverse event was an ADR. Identification of ADRs associated with long-term administration of drugs for chronic diseases also remains problematic. Methods to evaluate ADRs using data from clinical trials, medical records, and computerized databases of medication users and nonusers must be developed to complement spontaneous reporting systems. Without these methods, potentially important ADRs will remain undetected, and spurious associations between adverse outcomes and medications or devices will remain unchallenged.
Physicians and insurers need to weigh the effectiveness of new drugs against existing therapeutics in routine care to make decisions about treatment and formularies. Because Food and Drug Administration (FDA) approval of most new drugs requires demonstrating efficacy and safety against placebo, there is limited interest by manufacturers in conducting such head-to-head trials. Comparative effectiveness research seeks to provide head-to-head comparisons of treatment outcomes in routine care. Health-care utilization databases record drug use and selected health outcomes for large populations in a timely way and reflect routine care, and therefore may be the preferred data source for comparative effectiveness research. Confounding caused by selective prescribing based on indication, severity, and prognosis threatens the validity of non-randomized database studies that often have limited details on clinical information. Several recent developments may bring the field closer to acceptable validity, including approaches that exploit the concepts of proxy variables using high-dimensional propensity scores, within-patient variation of drug exposure using crossover designs, and between-provider variation in prescribing preference using instrumental variable (IV) analyses.
The Food and Drug Administration (FDA) is a regulatory agency within the Department of Health and Human Services. A key responsibility is to regulate the safety and effectiveness of drugs sold in the United States. FDA divides that responsibility into two phases: preapproval (premarket) and postapproval (postmarket). FDA reviews manufacturers' applications to market drugs in the United States; a drug may not be sold unless it has FDA approval. The agency continues its oversight of drug safety and effectiveness as long as the drug is on the market. Beginning with the Food and Drugs Act of 1906, Congress has incrementally refined and expanded FDA's responsibilities regarding drug approval and regulation.
In 2012, USA Food and Drug Administration (FDA) approved 39 new drugs, however, there are only two botanical drugs (one topical and one oral) approved by FDA since the publication of the FDA's industry guidelines for the botanical drug product in June 2004. The approval shows the Western guideline can be used for herbal medicines, authors investigate current regulation on herbal medicine clinical research, identify challenges conducting clinical trials, and seek to produce some guidance for potential investigators and sponsors considering a clinical trial in this area. Key words were formulated for searching on Medline and FDA website to locate relevant regulations for clinical research in herbal medicines to understand current environment for herbal medicine usage and examine the barriers affecting herbal medicine in clinical trials. Authors critically explore case study of the 1st FDA approved botanical drugs, Veregen (sinecatechins), green tea leaves extract, a topical cream for perianal and genital condyloma. In consideration of current regulation environment in USA, based on the findings and analysis through the literature review and Veregen case study, authors produce and propose a Checklist for New Drug Application of Herbal Medicines for potential investigators and sponsors considering in a herbal medicine clinical trial.
Use of herbal supplements is on the rise around the world, but limited data exist on the safety and efficacy of botanical products. Efforts to subject botanicals to rigorous scientific research began recently. There are many problems associated with botanicals research, however. These include procuring the study agents, selecting appropriate study method and clinical trial design, navigating through regulatory obstacles, and obtaining funding. Evidence-based botanical research can help to validate traditional uses and to facilitate new drug development. Concerted efforts of governmental agencies and industry are essential to ensure continuance of high-quality botanicals research.
Japan is unique among Asian countries in that it requires inclusion of substantial domestic clinical trial data in new drug application data packages. Some question the need for this and call for globalization of approved doses. The current study examines international differences in maximum daily dose of drugs approved in Japan between 2001 and 2007, and for all cardiovascular system (CVS) and central nervous system (CNS) drugs marketed in Japan. For 32% of the drugs approved in Japan between 2001 and 2007, the maximum recommended dose in the United States was > or =2 times higher than the maximum dose approved in Japan. Dose differences were rare for antitumor and antiviral drugs and also for priority-review and orphan drugs. Of all the price-listed CVS drugs currently available in Japan, 65% had maximum doses that were > or =2 times higher in the Netherlands than in Japan; similarly, 57% of the drugs had maximum doses that were > or =2 times higher in the United States than in Japan. For CNS drugs, these figures were 32% (the Netherlands) and 29% (United States). These results underscore the necessity to carry out quantitative analyses to determine the causes of these differences.
Herbal medicines have a long history of practice and hold great promise for treating human diseases. However, the traditional formula suffers many limitations that impede the fulfillment of their potential. There is, thus, a great need to transform traditional herbal medicines into Food and Drug Administration (FDA) approved modern botanical drugs. The current regulation of herbal medicines in the United States fails to provide sufficient incentives for the American drug industry to develop botanical drugs from herbal medicines. To provide such an incentive, this paper argues that the FDA should take into account the unique history and characteristics of herbal medicines, and adopt a special approval guideline for botanical drugs developed from these medicines. Such a guideline will facilitate the mainstreaming of herbal medicines in the United States, and at the same time alleviate the production crisis facing the American pharmaceutical industry. The paper then evaluates the recent FDA's Draft Guidance for Botanical Drug Products for its incentive effects on the industry and makes specific recommendations for the final version of the Guidance.
The United States Food and Drug Administration is charged with approving drug treatments that have been shown to be safe and effective. Relevant statutes and regulations provide a legal framework for establishing safety and effectiveness that is sufficiently flexible to ensure that appropriate scientific data are collected for specific treatments targeted to particular diseases. Nonetheless, all clinical trials proposed to establish effectiveness must incorporate common elements in order for the appropriate legal and scientific standards of drug approval to be met. This article will discuss the relevant laws and regulations pertaining to the current effectiveness standard and will discuss the most important clinical trial design elements currently considered acceptable for applications for treatments of neurologic and psychiatric illness.
Phase 0 clinical trials, developed in response to the United States Food and Drug Administration (FDA)'s recent exploratory Investigational New Drug (IND) guidance, are intended to expedite the clinical evaluation of new molecular entities. The exploratory IND supports the performance of first-in-human testing of new investigational agents at subtherapeutic doses based on reduced manufacturing and toxicologic requirements, allowing the demonstration of drug-target effects and assessment of pharmacokinetic-pharmacodynamic relationships in humans earlier in clinical development. The objectives of a phase 0 cancer clinical trial are to establish at the very earliest opportunity-before large numbers of patients have been accrued and exposed to potential drug-associated toxicity-whether an agent is modulating its target in a tumor, and consequently whether further clinical development is warranted. We review here the fundamental requirements of clinical studies conducted under an exploratory IND and address some common misconceptions regarding oncologic phase 0 trials.
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