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Indication For Patent Covered Drug Substances Biology Essay
Published: Last Edited:
This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.
The aim of this Bachelor Thesis is to analyse the different regulatory aspects for the marketing authorisation of a paediatric pharmaceutical product. In consideration of the duration of a patent various regulatory aspects must be measured when making a strategic decision on the point of submission according to the conduction of paediatric clinical trials.
In spite of the European Regulation No. 1901/2006 harmonising the regulatory and administrative process for the development of paediatric pharmaceutical products in Europe, there are still a lot of off-patent and patent-covered drugs used off-label, i.e. outside the approved indications or patient populations or unlicensed, i.e. a pharmaceutical product without marketing authorisation in the land of usage. The majority of pharmaceutical products is developed and evaluated in clinical trials by the pharmaceutical industry and used to obtain a marketing authorisation only for adults. Especially the application in younger children is based on historically experienced knowledge rather than reliable information about safety, quality and efficacy from clinical trials in the paediatric population.
In Germany about 88Â 000 medicinal products are authorised by authority. Only ten percent of these are authorised for the paediatric use.
Facing this problem, authorities granted various rewards and incentives like exclusivity rights to stimulate pharmaceutical companies in developing more pharmaceutical products for children, whereupon off-patent products get different incentives than patent-covered medicines. Therefore exclusivity rights also have to be considered when making a strategic decision.
A further issue is the paediatric population itself. Children of different ages differ in pharmacodynamics and pharmacokinetics resulting in the necessity of performing multiple clinical trials in the required age classes. Preterm newborn infants, for instance, need different dosages than adolescents, although both groups are part of the paediatric population.
The recruitment of participants for paediatric clinical trials is another effort for pharmaceutical companies, in particular for newborns and toddlers. Children need special care because of their developmental characteristics and sensitivity. As clinical research usually involves some risks to the subjects, mainly in the early stages, only well-prepared trials are ethically appropriate. Consequentially paediatric clinical trials need high attention and accurate organization as well as responsible handling.
Based on these introduced problems and opportunities, it is becoming more important to the pharmaceutical manufacturer to schedule a background test of a drug product from the beginning of the clinical trials until the approval of marketing authorisation, including the adequate regulatory strategy.
There are diverse considerations to be made by an entrepreneur in order to decide on a paediatric development programme. After a short extract of general aspects of Intellectual Property and Data Exclusivity, the following provides a description of special requirements needed for the conduction of clinical trials in the paediatric population. A key section describes the regulatory strategy for developing a schedule according to the conduction of paediatric clinical trials for patent-covered and off-patent pharmaceutical products. Afterwards, a timetable for the submission of the application will be created for the marketing authorisation of paediatric use. This plan will include the aspects of the conduction of paediatric clinical trials and the actual patent-situation as well as economic and marketing aspects of the regarding pharmaceutical product.
Finally a regulatory strategy for patent-covered drug substances will be proposed by summarising and evaluating the temporal process.
General Aspects
Pharmaceutical products used to treat the paediatric population should especially be aligned to ethical survey and be authorised for paediatric use. For getting a paediatric indication an application of the pharmaceutical company and the approval of the competent authority are required. In consequence an elaborated regulatory strategy is needed to follow the legal requirements and to get the best possible position for the launch of the new paediatric medicinal product.
With the intention of assessing the regulatory aspects of paediatric development for patent-covered drug substances, some basic facts should be summoned up. This includes features that make children exceptional for medical treatment as well as the present use of drug substances in the paediatric population. Furthermore the legal environment is described recording the appropriate European and National regulations and directives with special attention to the difficulties resulting from these.
The significance of children as special population for medical treatment
Minors, especially younger infants, represent a vulnerable population with physiological and pharmacological differences from adults. The most distinctive features differentiating children from adults are the significant physical and maturation changes, making development-related research of essential value. Therefore effects of many drug substances on the paediatric population may be different from the effects achieved in adults. Drug absorption, metabolism, and excretion substantially restrict the ability to extrapolate data from adults to children. The design of any clinical trial in children must take into consideration these important physiological distinctions.
Due to these reasons paediatric pharmaceutical products need to be tested systematically and intensely, ensuring that they are appropriate for the paediatric benefit. Clinical trials mandatory for this intention should be conducted relating to the best possible protection for the young patients.
Pharmacological characteristics
Children and adults differ in various pharmacologic aspects making an exclusive designed medical therapy for children extremely necessary. Even children differ among each other in physical development as well as metabolism depending from their age. Within its normal development the child's body is subject to profound transformations that affect the pharmacodynamics of a drug substance.
Above all pharmacokinetics in minors is the key aspect for a paediatric clinical trial. Pharmacokinetics refers to the processes of drug absorption, distribution, metabolism and elimination.
Drug absorption from the gastrointestinal tract is affected by gastric acid formation, bile salt secretion, gastric emptying time, intestinal motility, bowel length and effective absorptive surface as well as microbial flora. Since these parameters affiliate with the individual subject, a generalisation is difficult. Reduced gastric acid secretion increases bioavailability of acid-labile drugs (e.g. penicillin) and decreases bioavailability of weakly acidic drugs. Reduced bile salt formation decelerates bioavailability of lipophilic drugs. Drug absorption from injected drugs depends on the chemical characteristics, disparities in absorption by site of injection and alterability in muscle mass. Absorption from the lungs rather depends on reliability the device and patient or caregiver performance.
The distribution of a drug substance changes in children with ageing due to changes in body composition and plasma protein binding. Higher doses of water-soluble drug substances are required in younger infants because a higher percentage of body weight is water, conversely, lower doses are required to avoid toxicity as children grow older because of the decline in water as a percentage of body weight. Most drug substances bind to proteins, which is a limiting parameter for distribution. Decreased protein binding in newborns is also due to qualitative differences in binding proteins and to competitive binding by molecules (e.g. bilirubin) and free fatty acids, which circulate in higher concentrations in neonates and infants resulting in increased free drug concentrations, greater drug availability at receptor sites and consequently more rapid pharmacologic effects and higher frequency of adverse effects at lower drug concentrations.
Drug metabolism and drug elimination change with age and depend on the drug substance, at which many drug substances have extended plasma half-lives in infants compared to adults. The cytochrome P-450 enzyme system is the most relevant system for drug metabolism. These enzymes inactivate drug substances via oxidation, reduction, and hydrolysis (phase I metabolism) and hydroxylation and conjugation (phase II metabolism). Phase I activity is decreased in newborns, increases during the first six months of life, exceeds adult rates by the first few years for some drugs, slows during adolescence, and usually attains adult rates by late puberty. Phase II metabolism depends on the drug substance. Maturation of enzymes responsible for bilirubin and acetaminophen conjugation is delayed; enzymes responsible for morphine conjugation are fully mature even in preterm infants.
Drug substances are eliminated primarily through bile or the kidneys. Renal elimination depends on plasma protein binding, renal blood flow, and tubular secretion. All parameters are transformed in the first two years of life.
The following provides some examples to demonstrate this statement by describing essential characteristics and aspects.
Pre-term newborn infants suffer from an increased oxygen sensitivity, have less body fat, the quantity of water per kg of body weight is enlarged and the body-surface-area to weight ratio is higher than that of adults. Due to the immaturity of kidney the clearance is decreased and because of the increased body water a drug's volume of distribution is enlarged resulting in a prolonged half life. Dosage recommendations therefore should consider a prolongation of dosage intervals in contrast to older children.
The gastric pH of term newborn infants is more neutral than that of adults, the intestinal flora is more sensitive and the gastro-intestinal transit time is decelerated, consequential the absorption of drug is affected. Reduced gastric emptying and intestinal motility increase the time it takes to reach therapeutic concentrations when oral drugs are given to infants younger than three months. Furthermore term newborn infants do not have all enzymes needed for the metabolism of a drug. Especially in the first half year drug excretion is decelerated and the first-pass-effect is decreased. Above all the linking of a drug to glucuronic acid in liver is affected resulting in the risk of drug accumulation.
Toddlers are characterised of muscle- and skeleton-development and formation of the immune system. Due to a thin stratum corneum transdermal absorption may be increased in newborns and toddlers.
Children experience a progress in psychomotor domains and physical growth. They often have a higher metabolism rate due to an enlarged proportion of liver weight to body weight.
The adolescent phase is marked by the development of sexual maturity.
In order to reveal these different periods of paediatric development it is useful to make a distinction between various age groups. The ICH therefore classified the different age groups of the paediatric population in Topic E 11 (Table 3-1).
Table 3‑: Classification of the paediatric population according to ICH Topic E 11
pre-term newborn infants
0 to 27 days
term newborn infants
28 days to 23 months
infants and toddlers
2 to 11 years
12 to 16-18 years
Legal environment
During the last five years the European legislation on paediatric pharmaceuticals has fundamentally changed since making medicinal products available for the paediatric population involves extensive pharmaceutical and clinical efforts of the pharmaceutical company. The necessary research and development expenditures do not meet the expenses due to the small number of children affected by each disease in each age class. Accordingly the European governments decided to promote clinical development in children by granting incentives in the form of regulatory measures or other supporting measures. At this clinical research and development are respected as well as the ethical aspects of clinical trials in children, to make sure that new pharmaceutical products for children fit to the specific paediatric needs. The relevant legal requirements are presented in the successional section.
Regulatory framework
The various mechanisms of protection are important to put the different incentives, granted by the Regulation (EC) No 1901/2006, in context. Hence the following section gives a brief overview about these instruments, which are the basic for regulatory strategies in prolongation or achieving of different periods of exclusivity in order to prevent generic competition as long as possible.
Patent protection
Although no harmonisation of national patent laws has been taking place the European Patent Convention (EPC) alleviates the interaction between European and national law. It should be mentioned that the national law of a country deals with any infringements of a European patent. The European patent can be filed at the European Patent Office (EPO).
The duration of a European patent amounts 20Â years.
Supplementary Protection Certificate (SPC)
The Supplementary Protection Certificate is an intellectual property right, expanding the patent-protection beyond the validity of the patent. From the moment the patent expires, the SPC starts its protection. The maximum protection period of the SPC is 5Â years.
For research-based pharmaceutical companies, the SPC is the most important protection tool against generic competition. Although the protection offered by an SPC is limited to the protection the basic patent offered, the protection-period is of high commercial value.
The application for an SPC should be submitted within six months after the first marketing authorisation was granted when the following requirements are fulfilled:
protection by a basic patent in force
valid marketing authorisation
first application for SPC
first marketing authorisation as a medicinal product
Data and market exclusivity
Data exclusivity refers to protection of clinical test data. It includes an eight-year protection period for originator pharmaceuticals during which generic medicines may not refer to the information of the original marketing authorisation holder.
Market exclusivity refers to the ten-year period after which a generic product can be launched.
The Paediatric Regulation
The Paediatric Regulation (EC) No. 1901/2006 became effective in January 2007. It aims to improve the well-being of children in Europe by promoting clinical research in the paediatric population without delaying the authorisation of medicinal products in adults.
This is intended to be achieved through a system including combined measures of obligations and rewards and incentives, to motivate the development of paediatric drugs and to remunerate the industry for conducting the necessary investigation programmes. In fact, there are two types of benefits, namely substantive provisions, including rewards, incentives, providing free paediatric scientific advice, support and facilitating measures as well as procedural provisions, such as infrastructure, administrative procedures, legal and regulatory context.
In the course of stimulating research and development of medicines for children the regulation requires an agreement on the predetermined process for a new medicinal product, the so-called Paediatric Investigational Plan (PIP). The PIP should include detailed information of the trials to adapt the medicine's formulation for children, to cover the need of all paediatric age groups (Table 3-1) and a description of the study-times in children compared to these in adults. The investigational plan can be adapted throughout the trial, as knowledge expands. A pharmaceutical company submits an application for a PIP to the EMA's (European Medicines Agency) Paediatric Committee (PDCO). This Committee is in charge for judging the plan, i.e. agreeing or refusing it. Pharmaceutical companies are summoned to generate and submit a PIP at the end of phase I or II pharmacological studies.
In some cases, clinical trials can be deferred until the trials in adults have been conducted. This avoids a delay of the authorisation for adults. Even when trials are deferred, the PIP will take in details of these paediatric trials and their timelines. As some diseases do not affect infants (for instance Parkinson's disease), the research of drugs for these diseases should not be performed in minors. In such cases, a PIP is not required and will be waived.
An approval or waiver of the PIP by the Paediatric Committee is necessary in order to gain the marketing authorization and the appropriate incentives (Table 3-2).
Table 3‑: Overview of the incentives according to Regulation (EC) No 1901/2006
Medicinal Product with SPC or
Orphan Medicinal Product with
market exclusivity
Medicinal Product without SPC or
Extension of the SPC-period for 6Â months
Extension of the market exclusivity period for 2Â years
8Â years of
data protection
2Â years of
market exclusivity
Regulation Article
When all data have been submitted to the regulatory authorities, a pharmaceutical product with patent-protection or SPC will be granted an extension of the protection period for another six months. This extension will be conceded whether or not the additional clinical data result in a paediatric indication.
The incentive for orphan pharmaceutical products takes the form of another two years of market exclusivity.
The Paediatric Regulation also introduces a new type of marketing authorisation, the Paediatric Use Marketing Authorisation (PUMA). It is intended to boost the development of off-patent products for the exclusive use in the paediatric population. A PUMA must follow a Paediatric Investigational Plan and will benefit from eight years of data protection and another two years of market exclusivity.
All information about paediatric clinical trials shall be included in the European database (EudraCT) and all decisions of the European Medicines Agency on PIPs, deferrals or waivers of the paediatric programmes have to be made public and are published on the EMA website. Additional profits are the easing of recruitment of subjects, and avoiding unnecessary trials in children.
The present use of drug substances in the paediatric population
Children often suffer from the same diseases as adults and often are treated with the same medicals, nevertheless very few marketed pharmaceuticals are approved in clinical trials or have labelling information for the paediatric use.
Outcomes of adult clinical trials cannot be assigned to the outcomes of paediatric clinical trials, since there is no general norm for extrapolation, especially for the minimum and maximum dose, duration of efficacy, frequency and severity of adverse reactions. On this account an application to paediatric patients are not allowed if not mentioned explicitly in the dossier. The physician bears the full responsibility when though administering the drug, i.e. off-label, to help the young patients. This kind of an attempt to therapy is in Germany attributed to the Bundesärzteordnung §1(2): "The Aesculapian practice is no business, it is sui generis an independent profession." Nevertheless the off-label and unlicensed use of medicines in the treatment of children is not best clinical practice.
The main difficulties are the complications of carrying out clinical trials in children including ethical concerns, the variety of the paediatric population with the need to study subpopulations due to the limited size of the paediatric population, the complexity of developing paediatric forms and generally the cost of development for children. In the interest of the children the Paediatric Regulation was implemented in 2007. Since that time the number of scientific advices has increased, which means that pharmaceutical companies ask more and more for advice to prepare for paediatric clinical trials (Table 3-3). In the year 2011 129 paediatric clinical trials have been authorised. The trials themselves are to be conducted.
Table 3‑: Statistical overview of the implementation of the Paediatric Regulation from 2007 until 2011 by EMA
Paediatric scientific advice
PIP (validated applications)
Authorised paediatric clinical trials
Total number of clinical trials (adults and/or children)
Proportion of paediatric trials among all trials
10 %
9,9 %
In the years from 2007 to 2011 31Â initial marketing authorisations with a paediatric indication were granted, 39Â newly authorised paediatric indications for already authorised medicines were granted and 15Â newly authorised pharmaceutical forms for paediatric use for already authorised medicines were granted by EMA.
However, in March, 2012, the EMA issued a call for more clinical trials to be done in children. Despite 5Â years of the incentives implemented by the Paediatric Regulation to increase paediatric research, Agnès Saint Raymond, head of human medicines special areas at the EMA estimates that the number of clinical trials involving children has risen from 7-9Â % of trials in 2007 to around 12Â % in 2012.
Clinical Trials
A drug has to pass through several intricate and extensive stages of development until it gets its approval. During numerous preclinical and clinical trials the new substance will be monitored for efficacy, reliability, compatibility, dosage and possible interactions with other drug substances.
After successful testing in laboratory the active ingredient is going to be tested in various succeeding phases at humans. Therefore clinical trials are liable to demanding measures and surveillance. At this juncture the ethic issues are as important as the legal regulations. The safety of the patients always takes centre stage.
Clinical trials are conducted in phases, each with a different purpose (Table 4-1):
Preclinical Trials
Clinical Trials Phase I - Human Pharmacology
Clinical Trials Phase II - Therapeutic Exploratory
Clinical Trials Phase III - Therapeutic Confirmatory
Clinical Trials Phase IV - Therapeutic Use
Table 4‑: Overview of the Clinical Trials Phases
Preclinical Trials
cell-cultures, animals
Clinical Trials Phase I
voluntary, healthy humans
compatibility, dosage-finding
Clinical Trials Phase II
efficacy, adverse events,
Clinical Trials Phase III
comparison of the therapeutic
advantage opposite the standard
therapy and/or placebo
Clinical Trials Phase IV
optimal use, rare adverse events
General requirements for clinical trials
All phases of clinical investigation shall be designed, implemented and reported according to the principles of Good Clinical Practice intending the safety of subjects taking part in clinical trials.
A clinical trial in its intricacy obliges different phases for its performance. There are needs to be done before starting the trial, liabilities during the trial and several concluding duties at the end of the trial. These assignments are introduced subsequently.
Preliminary of a clinical trial
Designing a clinical trial requires a lot of various issues and criteria to be comprised. At first a short summary of the significant aspects is presented.
Study design
The study design is the essential foundation of the generated data's validity. An appropriate study design should accompany with the objective of a trial, which is to find out whether there is a dose range and schedule at which the drug can be shown to be simultaneously safe and effective, to the extent that the risk-benefit relationship is acceptable.
A study design may include parallel groups, cross-over, dose escalation, and dose response. It might be conducted placebo-controlled, blinded, double-blinded, randomised and multicentric.
Number of subjects
The volume of a clinical trial depends from the disease to be investigated, the objective of the trial and the trial termini. Statistical assessments of the number of the included subjects should be based on the expected extent of the treatment effect, the variability of the data, the specified probability of error and the need for information. In some cases a larger database may be needed to establish the safety of a drug.
Available information reveals that most adverse reactions first and often occur, within the first few months of drug treatment. There is a concern that some adverse reactions may occur only after drug treatment or may be more severe. Therefore 100Â patients exposed for at least one year is judged to be acceptable. The data should come from prospective trials designed to provide minimum one year exposure at dosage levels intended for clinical use. The total number of trial subjects including short-term exposure is anticipated about 1500.
Labelling of the investigational medicinal product
Each investigational medicinal product has to be labelled in a specific way to guarantee the identification of the medicine and ensure the correct appropriation. Furthermore the address and telephone number of the main contact for information should be included. All information should appear in the official language of the country in which the investigational medicinal product is to be used.
Investigator's Brochure
The Investigator's Brochure contains all information about the investigational medicinal product an investigator needs, i.e. data about the pharmaceutical quality as well as already acquired results from further clinical trials or known experiences from off-label use. It is in the sponsor's charge to keep the Investigator's Brochure updated and to supply the investigators and Ethic Committees with the current Investigator's Brochure.
Information for investigators
The Investigational Medicinal Product Dossier describes manufacturing and quality of the investigational medicinal product including reference- and placebo-products. Furthermore results of non-clinical and former clinical trials are included as well as a risk-benefit analysis of the investigational medicinal product.
Application for approval of a clinical trial at the NCA
The sponsor must submit the application in written form to the competent national authority and the competent Ethics Committee. All attachments can be supplied in either German or English language unless otherwise stated, whereupon application forms and attachments should also be supplied in electronic form. It is possible, but not mandatory, to file both applications in parallel. When submitting the documentation for a clinical trial; special forms for application, notification of later changes and end-of-study information are required.
At the example of Germany the documentation required by the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) and Ethics Committee involves:
copy of the confirmation letter for the EudraCT-number allocated by the EMA
signed cover letter in the German language with EudraCT-number, trial protocol number of the sponsor, title of the trial, information on specialities, and reference list of named information
study protocol signed by the principal investigator and sponsor / representative of sponsor with complete title, EudraCT-number, trial protocol number, version number and date
name and contact details of the sponsor and representatives in other EU/ EEA Member States
name and contact details of investigator sites, laboratories, main investigator and/or principle investigator
if an investigator is not a physician, professional background of investigator and reasons why her / his position is justified
information on investigators
name and characteristics of the investigational medication and its active ingredients
subject and objectives of the trial
number, age and sex of the subjects
criteria for selection of the people involved and statistical considerations
justification for selected distribution between sexes to determine possible gender-related differences of efficacy or safety of the drug
plan for follow-up treatment and medical care of patients after end of the trial
reasoned information on negative opinions of other Ethics Committees and non-approvals by other authorities
a declaration that subjects who do not agree about the circulation of their anonymised data will not be included in the trial.
Additional documents requested only by BfArM:
Investigational Medicinal Product Dossier (IMPD) with documentation about quality and manufacturing, as well as documentation about pharmacological-toxicological examinations, labelling, manufacturer authorisation, import licence, information about finished clinical trials, risk-benefit-analysis
certificate of assurance for xenogenic cell therapy
if genetically modified organisms are involved; an assessment of environmental risk, risk for non-treated subjects, observation plan for impact, measures to be taken for management and plans for cases of emergency
Name and contact details of the competent Ethics Committee and competent authorities in other Member States where the study will be conducted
The IMPD can be replaced by an approved Summary of Product Characteristics (SmPC) when the study medication already is authorised and intended to be used in the clinical trial in accordance with the SmPC ("on-label"). Otherwise, additional data regarding quality, pharmacology and toxicology must be provided, as well as results of further clinical trials.
If the medicinal product is used in a blinded trial, additional data concerning quality have to be provided. If the study medication is part of a clinical trial already approved by BfArM or PEI, the sponsor may refer to the data already submitted but has to provide all deviations. If the study medication is a placebo substance, only information concerning quality and manufacture is necessary.
Figure 4-1 shows the process of the submission of application for approval: The NCA must screen the clinical trial application within 10 days and acknowledge the formal validity or send a request for re-examination that has to be resolved within 14 days. In both cases the NCA sends at this step a confirmation of receipt for a valid submission. The application will then be re-screened with regard to contents. If the NCA sends a request for re-examination, the applicant has the chance to correct it once within 90 days. After having received the revised version the NCA approves the trial within 15 days or sends a final denial. If the application is correct, the NCA will approve the clinical trial within the 30 days after having sent the confirmation of receipt for pharmaceutical products listed in §42(2) para. 7 No. 2-4 of German Drug Law, within 14 days for phase I trials, within 90-180 days for genetic trials and without time-limit for xenogenic products. The Ethics Committee will be informed about the approval.
Application for an approving assessment of a clinical trial at the Ethics Committee
The Ethics Committee is an independent working party, consisting of healthcare professionals and laymen, whose responsibility is the protection of rights and safety of subjects involved in a trial. A clinical trial may be undertaken only if the clinical trial and the trial design are relevant, the anticipated benefits and risks are appropriate, the data presented are complete and the documentation presented complies with current scientific standards (including study protocol, investigator information etc). The Ethics Committee shall give its reasoned opinion within 60Â days from the date of receipt of a valid application to the applicant and the competent authority in the Member State concerned. A positive opinion of the Ethics Committee is mandatory for starting a trial.
In single centre trials, the application has to be submitted to the Ethics Committee of the principal investigator. In multi-centre trials, the application has to be sent to the Ethics Committee located at the coordinating investigator's place or in Germany, as exception, to the place of the "Leiter der Klinischen Prüfung". The "Ethics Committee in charge" coordinates the submission of the application. All other involved Ethics Committees should receive a copy of the application as well as all documentation.
At the example of Germany the documentation required by the Ethics Committee involves the documentation required by BfArM ad Ethics Committee (as mentioned before in "Application for approval of a clinical trial at the NCA") and additional data required only by Ethics Committee listed below:
annotations of the importance of the study
arrangement for the recruitment of subjects
declaration of the suitability of the supporting staff
information about the funding of the trial
information on investigators
economic interests of investigators concerning study drug (financial disclosure)
information about the quality of the facilities
documentation about sufficiency and totality of the information to be given and the specified process to be followed for the aim of obtaining informed consent and the explanation for the research on persons incapable to give informed consent
details of usual investigation methods and deviations
methods to be used to avoid parallel participation of subjects in other clinical trials
insurance or indemnity to cover the liability of the investigator and sponsor
amounts for annealing or compensating investigators and subjects
declaration for the compliance of data protection
details of the contracts to be made between sponsor and facilities
criteria for the interruption or preterm termination of a trial
list of Ethics Committees involved (in the case of a multi-centre study)
if the protocol is provided in English, a summary of the important parts in the German language is required.
Also displayed in Figure 4-1 is the submission of application for an approving assessment of the Ethics Committee: The Ethics Committee has to screen the clinical trial application within 10 days and acknowledge the formal validity or send a request for re-examination that has to be resolved within 14 days. Then the Ethics Committee sends a confirmation of receipt for a valid application. The submission will then be re-screened with regard to contents. Within 30 days after having sent the confirmation of receipt for pharmaceutical products listed in §42(2) para. 7 No. 2-4 of German Drug Law, within 14 days for phase I trials, within 90-180 days for genetic trials and without time-limit for xenogenic products the Ethics Committee will send a reasoned opinion to applicant and NCA.
Figure 4‑: Overview of the regulatory deadlines of an initial submission of a clinical trial to the National Competent Authority and Ethics Committee according to GCP-V
Public registration and request for EudraCT number
Any clinical trials in the European Union have to be registered in the EudraCT database. This database was implemented by the EMA for ensuring the transparency of the conduction of Clinical Trials as well as the monitoring of the subjects' safety. A EudraCT number has to be allocated by the EMA before submitting the application for conduction of a clinical trial.
Informed consent
Every patient has to be informed comprehensively before participating in a clinical trial. The duty for informing patients and for obtaining a informed consent in written form as well as the content of the patient's information concerning her respectively his participation in the trial are ordered inter alia by the German Drug Law, the GCP-V, the ICH guideline and the EU directive 2001/20/EC. Furthermore every subject has to agree to the survey, handling and transfer of her respectively his (anonymised) data. Majority age, for instance, is an additional criterion for participating in phase I trials.
Clinical trials insurance
For the submission dossier of a clinical trial it is necessary to insure all participating subjects. In Germany investigators additionally need a professional indemnity insurance.
Obligations during the trial
During a clinical trial sponsor and investigators are obliged to keep the authorities updated in any questions concerning protocol-changes after approval, serious adverse reactions and suspected unexpected serious adverse reactions. Furthermore the authorities have to be provided with an annual safety report as well as a development safety update report, subsequently characterised.
Changes after approval
All changes after approval concerning patient safety, interpretation of the scientific data, trial outcome, trial management, quality or safety of the investigational medication and risk assessment must be approved by both the NCA and the Ethics Committee (Figure 4-2). Approval is considered to be given if NCA does not reject within 20Â days. Proposed or requested modifications from NCA should be implemented within 35Â days. The Ethics Committees must approve or disapprove these substantial amendments within 20Â days. Additional sites can only be included if the Ethics Committee in charge gives approval (within 20, max. 35Â days according to the investigational medicinal product). The Ethics Committee is responsible for informing the NCA of its decision.
Non-substantial Amendments have to be agreed only by Ethics Committee nevertheless the BfArM must be informed.
Figure 4‑: Overview of the regulatory deadlines of a Substantial Amendment Application to the National Competent Authority and Ethics Committee according to GCP-V
Notification of Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions (SUSARs)
A Suspected Unexpected Serious Adverse Reaction is a serious adverse reaction which is not expected in the trial and which also is potentially correlated to the investigational drug substance and therefore could represent a side effect. A serious adverse reaction is characterised as any objectionable medical effect that results in death of a subject, is life-threatening, necessitates hospitalisation or extension of hospitalisation, results in permanent disability or is inherent.
The sponsor must record and submit all adverse reactions to the NCA, Ethics Committees, other authorities in the EU and investigators upon request within 15Â days whereupon individual subject data should be anonymised. All SUSARs that resulted in death of a patient must be reported to the NCA, Ethics Committees, other authorities in the EU and investigators within 7Â days. All facts concerning single cases of known but serious adverse reactions with unexpected outcome, change of incidence of known but serious adverse reactions with clinical relevance, SUSARs when the patient concerned has already finished the trial, all other events that may influence the safety of the concerned subjects, and therefore may lead to a reassessment of the risk-benefit must be reported to the NCA, Ethics Committees, other authorities in EU and investigators within 15Â days.
Annual Safety Report
The sponsor has to submit to NCA, Ethics Committees, other authorities in the EU and investigators a list of serious adverse reactions and the safety of the concerned patients once a year or upon request as long as the trial continues.
Development Safety Update Report (DSUR)
The Development Safety Update Report is an annual report of all ongoing or terminated clinical trials. It contains both cumulative and interval safety information relating to the investigational drug.
Liabilities at the end of trial
The conclusion of the trial must be reported within 90Â days to the NCA, Ethics Committees and other authorities in the EU. A summary report with relevant results should be forwarded to the Ethics Committees and the NCA within one year. All data must be archived for 10Â years.
The biometric and statistic evaluation shall be performed with the statistical methods defined in the protocol. Only after evaluation of the analysis, the blinding-code may be opened.
The sponsor is in charge for archiving the most important documents of the clinical trial. Essential documents should be retained at least 10Â years, the subject-identification-list for 15Â years after the end of the trial, the Trial Master File, which contains all data generated during the clinical trial, as long as the medical product is authorised and the synopsis until five years after the medical product is no longer authorised.
After the end-of-trial-protocol is finished, a combined publication has to be prepared. It should contain positive as well as negative outcomes of the trial.
General difficulties in paediatric clinical development
A working group of the European Commission recommended a list of issues to be considered for planning a paediatric trial: "
Identification and scientific validity of the study question to be answered
Justification of the study to be performed in children and in the proposed age groups
Evidence of direct benefit for the child, or benefit for the group
The competence of the responsible study investigator and his/her team
The infrastructure of the institution or primary care practice that should be qualified and experienced in paediatric research in general and in particular in the field of the applied project.
The pre-clinical safety and efficacy data (investigator's brochure, available literature) that are preconditions for a paediatric clinical trial
The clinical results of adult studies (literature, investigator's brochure), if any.
Type and phase of the study
Use of placebo or active control
Age-appropriate formulations of medicinal products
Age-appropriate scales or measures of end-points (e.g., pain scale)
Study design and biometric planning in relation to the trial question
Design feasibility and information sheets checked with children / patient representatives
Inclusion and exclusion criteria
Statistical methods
Criteria for the termination of the study
Safety measures including the set-up of a Data Safety and Monitoring Board (DSMB)
Appropriate pharmacovigilance procedures are put in place by the sponsor
Study risks, pain, fear and discomfort
The potential risks (real and theoretical) have been weighed against the expected benefits for the children enrolled in the clinical trial. The balance of expected benefit versus risks should be positive for the clinical trial.
Comprehensive, understandable Informed Consent and Information sheets for legal representatives
Understandable age specific Informed Assent and Information sheet for children
Anonymity of the data, as well as confidentiality of personal information related to the child involved in the research, and to her / his family
Insurance of child participants, in the relevant country
If available, opinions of other ethics committees for international multicentre studies
Publication of trial results
Continuation of trial medication where appropriate"
Some of the special differences between adult and paediatric trials shall be characterised in the following sections.
When results can be achieved in trials with adults, children should not be included in clinical trials. If research with minors turns out to be necessary the least vulnerable among them should be included (i.e. older children).
For a clinical trial in healthy minors the investigational medicinal product must be designed for the identification or prevention of diseases in minors and clinical trials in adults must have been insufficient for a paediatric application. Clinical trials in diseased minors can only be performed under the premise of saving the patient's life, to assuage the distress, to help other individuals in the same group of patients suffering from the same disease and if the liability is minimal. Furthermore results from repeated-dose toxicity studies of appropriate duration in adult animals, genotoxicity tests and safety data from previous adult human experience should be available before initiating a paediatric clinical trial.
Since children cannot consent, the use of placebo is quite limited. Placebo often is necessary to demonstrate the efficacy of a new drug, also in paediatric trials. However, placebo should not be used in children for serious and life-threatening circumstances but may be used when facts for any treatment are missing. The use of placebo is not the same as deficiency of treatment, for instance placebo could be used in addition to standard therapy. In any circumstances placebo use should avoid or minimise harm. Placebo as comparative substance may be used for diseases without commonly accepted standard therapy and the investigational new drug is the first one for that disease.
Appropriate dosage forms
One problem and at the same time indication for a paediatric clinical trial that complicates drug therapy in children is the absence of suitable dosage forms. The administration of a medicinal product to infants and children may require special dosage forms designed for that purpose.
In general for the oral route liquid formulations are the preferred therapy since in this way the variability of the required dose for various age groups can be assured. For drug substances where only a solid dosage form exists, parents often must divide tablets for adults to get the correct dose for their child. This may lead to inaccurate dosing that can result in amendable therapeutic response. Furthermore, substances may be selected for special criteria like a suitable taste for children.
As a result there is a request for paediatric formulations allowing exact dosing and ensuring the compliance. The individual target age groups should be considered early in the course of paediatric drug development. The range of paediatric formulations could include liquids, suppositories, transdermal patches, nasal sprays or solutions for injection.
Study design
All measures to avoid bias should be respected in paediatric trials as in trials with adults. For instance, blinded or controlled clinical trials for the demonstration of efficacy are parameters to decreased bias and should be used.
The trial's size should be as small as possible but large enough to display the appropriate efficacy with adequate statistical power.
Informed consent assent???
As this age-group is not sui juris until reaching an age of seven, getting an informed consent for a clinical trial is quite complex. The legal guardian must be informed and educated about the trial before giving consent. If the minor is able to understand significance and consequences of the trial, she respectively he must also be informed and asked for consent, too. As mentioned before, children, having not yet reached the majority age, are not allowed to participate in phase I trials. There is only one exception from this regulation, namely a palliative care situation. A terminally ill child may enter a phase I trial if the possibility of advantage from the new ingredient is equivalent to that of palliative therapy or prolongation of the failed treatment.
Recruitment of subjects
The Paediatric Regulation encourages pharmaceutical companies to carry out paediatric clinical trials. Concerning these trials there is a huge difficulty for the pharmaceutical developer next to the financial and administrative challenges, the children themselves. Paediatric recruitment encloses the problem of finding enough minors in the fitting age-class with the corresponding disease and getting an informed consent by child and parents.
A survey identified the causes for parents and children for not taking part in a paediatric clinical trial. Time was the most important criterion followed by the unwillingness of parents and children entering a trial. Further reasons were the timidity of the children, foreign language or health issues. Another investigation found out that the child's safety was a big reason. These explanations contribute to the fact that in paediatric trials only a very small number of minor subjects may be recruited.
Minimising distress
If procurable, physical and emotional pain should be avoided. Pain may occur due to the disease itself or due to the medical intervention (e.g. blood sampling). Dolorous actions should be minimised as far as possible. An age-based explanation always should be given to the child before the investigation to minimise fear. In order to minimise pain, distress, and fear, the environment should be suitable for children, i.e. toys, activities, furniture. Furthermore the staff should be trained to look after children and their needs and be skilled to perform paediatric procedures.
To avoid a replication of clinical trials in the paediatric population the Paediatric Regulation requires a publication of the description of clinical trials as well as their results independent from the outcome in the EMA's EudraCT database.
Regulatory background
Approval Procedures for Marketing Authorisation
In abidance by the regulations and directives pharmaceutical companies may choose the approval procedure corresponding to the target market. In the European Union, medicines can be authorized by the EMA, which grants a Europe-wide marketing authorisation or by the national competent authority for a national marketing authorisation. A general overview of the national and European Approval procedures for marketing authorisation is represented in Table 5-1 and Figure 5-1. Table 5-1 shows the legal background of each procedure, the kind of aspired marketing authorisation as well as the pre-conditions to be fulfilled for choosing the correspondent approval procedure. The process of each procedure is then displayed in Figure 5-1. It contains the fixed timelines as described in the following sections and an appraisal for the estimated time to market, i.e. the time for obtaining a marketing authorisation.
Table 5‑: Overview of the Approval Procedures for Marketing Authorisation
National Law
Regulation (EC) No. 726/2004
Directive 2001/83/EC
Directive 2004/27/EC
Country of the Approval
All EU-
Member States
EU-Member States
participating in the procedure
EU-Member States
participating in the procedure
biotechnological product,
orphan medicinal product, product containing a new active substance which is intended for the treatment of AIDS, cancer,
neurodegenerative disorder or diabetes
is existing
No national
is existing
National Procedure (NP)
Each EU Member State has its own procedures for the authorisation of medicines. A national approval procedure lasts about two or three years, which is beside the target market another reason for choosing a European approval procedure, which are fixed in a detailed timetable.
Centralised Procedure (CP)
The CP is mandatory for medicinal products manufactured using biotechnological processes, for orphan medicinal products and for products containing a new active substance which is intended for the treatment of Acquired Immuno Deficiency Syndrome, cancer, neurodegenerative disorder or diabetes. Optional it can be chosen for products containing new active substances, for products which represent a significant therapeutic, scientific or technical innovation, for generics of centrally authorised products and products for which a central authorisation is in the interests of patients.
Thereby all applications are directly addressed to the EMA in London. The procedure results in a European Commission decision, which is simultaneously valid in all EU Member States. Centrally-authorised products may be launched in all EU-Member States.
The CP hews to a fixed timetable. The procedure starts at Day 1 and ends at Day 210, which leads in best case to a European Commission Decision at Day 285 and thus to a marketing authorisation by EMA.
Mutual Recognition Procedure (MRP)
For the Mutual Recognition Procedure a medicine first has to be authorised in one EU Member State, in accordance with the national procedures of that country. Following this, other countries can agree to recognise the validity of the original, national marketing authorisation.
An application for Mutual Recognition is to be addressed to the national competent authority of one or more Member States. It must be identical and Member States must be notified of them. Result of the MRP is the national marketing authorisation in every in the procedure participating Member State. The MRP begins at Day -14 with the submission of the dossier to the national authorities of the participating Member States. The procedure starts at Day 0. Due to the existing national marketing authorisation the procedure only takes ninety days. When a consensus is reached, the procedure ends at Day 120 with the granting of a national marketing authorisation in each participating Member States. If a consensus cannot be reached, the points of disagreement are referred to the CMD(h). If again a consensus cannot be reached the process is referred to the CHMP for arbitration.
Decentralised Procedure (DCP)
Using the Decentralised Procedure, companies may apply for simultaneous marketing authorisation in more than one EU Member State. A DCP can be initiated for products that have not yet been nationally authorised in any EU State and that do not fall within the obligatory scope of the centralised procedure. The following steps are identical to the MRP.
As in the MRP, the result of the DCP is a national marketing authorization in every participating Member State. The DCP like the other European procedures follows a fixed timetable. It begins at Day -14 with the submission of the dossier to the national authorities of the Member States. When the procedure starts at Day 0 all information about the complete dossier must be discussed since this is the initial submission for authorisation. So the procedure can only be closed, when a consensus is reached. If a consensus cannot be reached, a Breakout Group of involved Member States reaches a consensus on the matter.
Figure 5‑: Presentation of the approval procedures and the correspondent expected time for obtaining a Marketing Authorisation
Regulatory conditions for clinical trials
As described in detail in section 4.1(Titel??) a lot of regulatory endeavours have to be made by a pharmaceutical company to get the authorisation to conduct a clinical trial. Especially the conduction of paediatric clinical trials is closely regulated. Table 5-2 contains a listing of several relevant ICH and EMA-guidelines to be observed for the conduction of a clinical trial in the paediatric population.
Table 5‑: ICH- and EMA-guidelines for paediatric drug development
Periodic Safety Update Reports for Marketed Drugs
Pharmacovigilance Planning
Development Safety Update Report
Structure and Content of Clinical Study Reports
Dose Response Information to Support Drug Registration
Ethnic Factors in the Acceptability of Foreign Clinical Data
Guideline for Good Clinical Practice
General Considerations for Clinical Trials
Statistical Principles for Clinical Trials
Issues in Clinical Trials
Clinical Investigation of Medicinal Products in the Paediatric Population
Human Clinical Trials and Marketing Authorisation for Pharmaceuticals
Stability Testing
Validation of Analytical Procedures
Impurity Testing
Pharmaceutical Development
Development and Manufacture of Drug Substances
Guideline on Clinical Trials in small Populations
Discussion Paper on the Impact of Renal Immaturity when investigating Medicinal Products intended for Paediatric Use
European Medicines Agency policy on changes in scope of paediatric investigation plan (PIP) decisions
Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate
Guideline on the Role of Pharmacokinetics in the Development of Medicinal Products in the Paediatric Population
Concept Paper on the Need for the Development of a Paediatric Addendum to the Note for Guidance on the Clinical Investigation on Medicinal Products in the Treatment of Hypertension
Concept Paper on the Impact of Liver Immaturity when investigating Medicinal Products intended for Neonatal Use
Official Journal of the European Union. Communication from the Commission: Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies
The numerous papers mirror the need of the pharmaceutical industry to receive scientific and technical guidance to realise the quite complex and diverse regulatory requirements. Harmonising the requirements for paediatric trials will reduce duplicate studies and thereby reduce the number of children exposed to a clinical trial. The guidelines form a compendium in paediatric drug development as well as harmonisations for a safe, efficient and ethical examination of medicinal products in the paediatric population.
Even though guidelines and directives cover the important criteria, a regulatory strategy depends on various aspects like active ingredient, disease and the paediatric population itself. In consequence clinical trials in children need special attention and accuracy for planning and conduction.
Regulatory Strategy
There are a range of considerations to be made by a pharmaceutical company in order to settle on a product-specific paediatric development programme for patent-covered drug substances.
As described in section 3.2.2 (Paediatric Regulation), for every innovative drug substance a Paediatric Investigation Plan has to be submitted to the national competent authority when applying for a Marketing Authorisation. Furthermore as explained in section 5.1 (Approval Procedure), an innovative drug substance has to be submitted in the Centralised Procedure to the EMA as competent authority. Since this approval procedure is regulated in detail, the pharmaceutical company must follow the given regulations. On this account a regulatory strategy for obtaining a paediatric indication for innovative patent-covered drug substances is not useful. However, a regulatory strategy for obtaining a paediatric indication is absolutely necessary for patent-covered drug substances already authorised for adult patients, since there are several possibilities to prolong intellectual property and market exclusivity.
Planning for submission - Selection for application procedure
One of the key aspects is time to market. From the commercial point of view it is fundamental to launch the product as soon as possible in order to obtain the longest possible market exclusivity.
Timing of studies
The risk of conducting studies in children versus the benefit to paediatric patients is basic to the decision for initiating paediatric clinical trials during a drug development programme. The decision on timing primarily depends on therapeutic need and the availability of alternative medicines. The ICH Topic EÂ 11 guideline classifies three steps of significance for conducting trials in children.
The first step includes medicinal products for diseases preferentially or exclusively affecting the paediatric population. In this case, the entire development programme will be conducted in the paediatric patients except for tolerability and safety data, which usually will be obtained in adults. The ICH recommends that studies in children should proceed immediately following the initial pharmacokinetic, safety, and efficacy studies in adults (Phase I and early Phase II). However, compounds designed exclusively for paediatrics should be evaluated in children earlier in medicinal product development.
The second step for initiating a paediatric clinical trial refers to medicinal products proposed to treat serious or life-threatening diseases, occurring in adult and paediatric patients, for which there are at present no or provisory therapeutic options. Evidence of safety and reasonable efficacy (Phase I and Phase II) in adults should precede directly paediatric trials or may be started in parallel with the paediatric trial, and data from these trials should be incorporated into the paediatric marketing application.
The third step is about medicinal products intended to treat other diseases and conditions. It is rec

subset: commoncrawl


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Wand Corporation |
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Sunday, October 27, 2013
New giveaway! Now I'm giving away Rodeo Queen by Shannon Taylor Vannatter!
Caitlyn Wentworth loves being a rodeo queen...
Until she starts receiving threatening letters from a stalker. The good news is, the Texas Ranger assigned to her case is none other than her former sweetheart Mitch Warren; the man who chose his career over love.
Mitch vows to focus on protecting the woman he's never forgotten. But Caitlyn stirs up memories best left in the past. When Mitch insists on hiding Caitlyn away on his family's San Antonio ranch, will he keep things professional or seek out a second chance?
And now for the question...Have you ever been to a live rodeo? If yes, what was your favorite event?
9 comments:
- Katrina E. said...
Yes, I attended a rodeo in Wyoming in the '90s. I love the bull riding. That was the same year Lane Frost died. What a loss to the circuit. I love Tuff also.
email@example.com - 7:43 AM
- Jamie Leigh Martin said...
Nope, but I've always wanted to go!!
email@example.com - 2:46 PM
- Anita Yancey said...
I have never been to a rodeo, but I hope to in the near future.
ayancey1974(at)gmail(dot)com - 6:06 AM
I have only been to one rodeo and I prefer bronco riding to bull riding. Both are dangerous, but it seems to me that broco riding would be somewhat safer. I like watching the instant the bucking chute opens and man and horse lurch forward. Staying on the horse for 8 seconds seems easy, but it isn't.
- Martha Lawson said...
I've never been to a rodeo, guess I'd better put it on the bucket list!! I love saddle bronc and bull riding. Thanks for the chance to win this book.
mlawson17 at hotmail dot com - 12:51 PM
- windycindy said...
No, I have never been to a live rodeo...It is on my bucket list, though.
Many thanks, Cindi
jchoppes[at]hotmail[dot]com - 5:26 PM
- Merry said...
Yes, my Dad and my husband enjoy rodeo. I like the barrel racing the best. Thanks for the chance to win Rodeo Queen, I've been enjoying this series.
worthy2bpraised at gmail dot com - 8:19 AM
- Michelle Sutton said...
and the winner is... Katrina
- Shannon Taylor Vannatter said...
Hey y'all,
I guess I got started writing rodeo books because my dad announced at a very small rodeo in our town and I worked in the concession stand. I didn't think about it until years later when I saw a cowboy to the bone guy holding hands with a girl dressed in a business suit at the State Fair of Arkansas. I wondered what they had in common and that wondering became the first book in this series. And I'm a lot like the heroine in that book - bulls terrify her. They make me really nervous. When my family and I went to Cowtown Coliseum at the Fort Worth Stockyards to research the series, I was a nervous wreck through the bronc and bull riding.
Congratulations Katrina and I appreciate everyone for stopping in. - 4:23 PM


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Decimal Degrees: Latitude: 36.4334004 Longitude: -93.4168518
Share your comments and photos of Township of North Yocum, a Civil in Carroll County, AR
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Cemetery: Blue Eye Cemetery
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"Smartphone technology is penetrating world markets and becoming abundant in most college settings," said Philip Kortum, assistant professor of psychology at Rice University in Houston and the study's co-author. Latest News from Lifestyle News Desk
"We were interested to see how students with no prior experience using smartphones thought they impacted their education," said Kortum.
The research shows that while users initially believed the mobile devices would improve their ability to perform well with homework and tests and ultimately get better grades, the opposite was reported at the end of the study.
The longitudinal study from 2010 to 2011 focused on 24 first-time smartphone users at a major research university in Texas.
Prior to the study, the participants were given no training on smartphone use and were asked to answer several questions about how they thought a smartphone would impact their school-related tasks.
The students then received smartphones, and their phone use was monitored during the following year. At the end of the study, the students answered the same questions.
Kortum noted that the study did not address the structured use of smartphones in an educational setting. He said that the study's findings have important implications for the use of technology in education.
"Previous studies have provided ample evidence that when smartphones are used with specific learning objects in mind, they can significantly enhance the learning experience," Kortum said.
"However, our research clearly demonstrates that simply providing access to a smartphone, without specific directed learning activities, may actually be detrimental to the overall learning process," Kortum added.
The research appeared in the British Journal of Educational Technology.


text:
Lincolnshire Showground is located two miles North of Lincoln via the A46 Lincoln by-pass. The main entrance to the Showground is at Gate 1, immediatley off the A15. The postcode is LN2 2NA.
Entrance Fees
Trade Entry: 7:00am - 9:00am - Free entry with a trade business card
Public Entry: 9:00am - 3:00pm - £2 per person
Accompanied under 16s are admitted free.
Management reserve the right to refuse admission on the door without reason.


text:
Operators of pre-2007 trucks who currently operate in California have some tough choices coming with CARB's truck emissions rules -- here are some ways to think about them to help navigate.
Read MoreMore and more, owner-operators are choosing to hold on to high-performing older equipment and run routes that keep them far away from the Golden State rather than upgrade to meet CARB emissions requirements.
Read MoreVehicle personalization is human nature, but why in the world people feel compelled to tell the entire world their preference in eyewear and portable beverage refrigeration systems...
Read More


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Warning: the topic discussed below may not be everyone's cup of tea. Because so many people have asked about composting toilets, wanting to know some pretty detailed stuff, I do need to talk about human waste in a bit of detail below.
If you'd prefer to just to skip the potty talk and just read the upshot, here it is:
Composting toilets…
…do not require a connection to a private or municipal septic system, and are therefore often much, much less expensive to install and easier to use in a non-traditional (Tiny, Accessory, Off-Grid) home, even though the toilets themselves are more expensive than "traditional" toilets.
…do not smell.
…do require some maintenance (i.e. emptying), which can range from a few times a month to a few times ever, depending on the system.
…produce material that is excellent for flower and vegetable gardens.
…range in perceived grossness between "I never would have guessed it's not a typical toilet!" to "You have a porta-potty in your house?"
Now, for the nitty gritty:
Maybe the most fundamental mentality change between contemporary global eco-consciousness and what came before is the desire to work with, rather than only against, nature. Without much change in people's lifestyles and desires, nearly everyone is on board with using the sun's energy, harnessing the wind's power, and taking advantage of wave motion. On the slightly techier side of things, hybrid electric cars use residual wheel momentum to charge batteries, taking Newtonian waste and converting it to the electric equivalent of black gold. Another "black gold," at least in gardening circles, is compost. Generally speaking, "compost" is nutrient-rich dirt that has recently decomposed and which is probably the most important "additive" for healthy, robust flowers and vegitables. A swiftly growing percentage of Americans now have 3 pails under their kitchen sink: trash, recycling, and compost – the last of these being where they toss banana peels, bread crusts, and nearly any natural material besides meat.
If those three pails happen to be neglected for a summer, opening the under-sink cabinet would reveal a trash pail that smells like death, a recycling pail that is no different than they left it, and a compost pail that is now full of sweet, frankly great, smelling soil – compost! This is added to gardens often along with another miracle of decomposition – cow manure. We've all driven through agricultural areas where the smell of cow crap, um, perfumes the air. While some claim to like the smell, the uninitiated typically roll up their windows. And, nearly everyone has used manure-based fertilizers for planting or gardening… Notice there's no poop smell? That's the magic of composting.
This leads us to human manure (or "humanure", as Joseph Jenkins calls it in his similarly entitled, very famous book on the topic). Human poop does have bacteria and other nasty stuff in it. But, allowed to sit for a while, and ideally laced with a little bit of dirt, sawdust, or commercial "compost starter," it stops smelling and becomes Black Gold, ready to be used in growing your tomatoes and other delectables. So much has been written about this process – including Jenkin's canonical book – that I won't even try to add to the topic. If you are interested, I urge you to browse some of the links I've included at the bottom of this post.
You may have noticed the words, "allowed to sit for a while," in the above paragraph. That's all fine, but until then, will your bathroom/house smell like sh*t? The vast consensus from those who own halfway decent composting toilets is "No!" In fact, many owners of composting toilets can't believe how bad their friends' and family's bathrooms smell when they are second in line to the loo. I won't comment on my own family, but I will say that this seemingly ironical issue does make scientific sense. Most modern composting toilets (such as those we include as options in its DIY home kits) contain a fan that effectively sucks air (and the smells it contains) directly out from the toilet. Without the air, there can be no smell. It's not like air fresheners which cover (often imperfectly) smells. These fans literally suck the stink out of the toilet. This secret smell-killing weapon cannot be replicated with flush toilets because of the water in the tank, which is why that smell makes its way throughout your bathroom, even though you flushed.
This all being said, there's for some people a unique downside to composting toilets – whether all-in-one units that are toilet and composting chamber in one or whether two-part units where the refuse is stored in a larger, separate tank outside or in the basement, they all need to be emptied every once in a while. Depending on the system and size of the tank, frequency varies from 3-4 times a month for a family using an all-in-one "compact" system to a half-decade for those with two-part systems. Because the process of composting reduces the volume of "material" in your tank, and because it doesn't smell (remember from the three pails under the sink: composting, unlike sitting garbage, smells better as it decomposes), it's simply a matter of emptying the tank when it's full (Although, I wouldn't push the limit too far, as you do need air in the tank for composting to happen.) If you are emptying your tank monthly or more frequently, you either toss the fresh compost into your flower beds or hold it in a larger, outdoor container or pile (a compost bin/pile) for another few months before using it in your vegetable garden. With a two-part system, the compost has sat long enough that it is "vegi-ready". If you have neither a the green thumb or a green property, I suppose you can just "throw out" your compost, though you're wasting some good stuff that will just fill up your local landfill. (If you are tossing your black gold, consider first donating it to a neighbor – just don't light it on fire on their front steps!)
The other difference between "regular" toilets and the composting variety is that most of the latter are dry-bowl systems. They are Teflon-y to be sure, but it's still likely that, without the steps I mention below, you're business might be known to the next customer. While some fancier systems use foam flushing techniques that solve this issue quite well, you can alternatively use a spray bottle with natural soap cleaner. Finally, some composting toilet bowls are black on the inside, which is a more, um, "artistic" way of dealing with the problem.
At this point, it's also worth mentioning what you see if you look down into your composting toilet. This depends on the unit. The absolute most basic systems are similar to a porta-potty in this respect – you can see into the past, but in the composting version, the past now looks mostly like dirt. Others are similar to airplane toilets (with or without water/foam flush) – there's a trap door that closes the portal to what went down before. (One brand, Separett, has a trap door that opens when you sit and closes when you get up, hiding your business even from you!) Finally, two-part systems (separate tank) hold the waste somewhere else, so no issue there either.
Moving on to number 1, this stuff is even more potent as a fertilizer. In fact, urine is primarily nitrogen, which is the main ingredient in commercial fertilizer. The most basic composting systems don't differentiate between liquid and solid waste. However, most "modern" composting toilets separate the two (basically, there's an area for each in the toilet bowl, located in such a way as to be comfortably used by both women and men.) The urine either goes into a separate holding tank or directly to the outside of your home via a filter of some sort (at its most basic, we're talking a little tube that pokes out the bottom of your house and goes into a hole filled with rocks in the ground). Other systems, however, do need to be emptied from time to time, and there are many options depending on how often you are willing to empty the tank and how close you want to get to the liquid while do so. And, again, if you have a green thumb, you'll appreciate this super-fertilizer that you can just dump into your garden. To think, it only cost the price of a Diet Coke!
Do I believe that Composting Toilets are going to replace septic systems in the near future – no, I don't. Throughout the world, however, countless gallons of fresh, clean drinking water is mixed with top shelf potting soil and the organic equivalent of liquid miracle grow – in the process rendering all three of these useless. I personally hope that the composting ethos being employed by an increasing number of homesteaders, road warriors, tree huggers, and just, plain old conscientious citizens will trickle up to municipalities designing ways to improve the efficacy, cleanliness, and rationality of their town sewage systems. In the meantime, home-based composting toilets are an inexpensive and fairly easy way to unplug but still tune in.
Thanks for reading, and feel free to post questions below.
(Co-founder, Homebuilt)
Resources for further information:
Wikipedia article on composting toilets: http://tinyurl.com/plf5sg3
More on the non-stinkiness of composting toilets, by a scientist: http://tinyurl.com/qfukvnw
Candide and pragmatic post by Tiny House owner & composting toilet user: http://tinyurl.com/p8hv59z
Website of the humanure guru, Joseph Jenkins: http://humanurehandbook.com/
Reddit discussion about whether composting toilets smell: http://tinyurl.com/ndzdwnn
Scientifically validated explanation of urine fertilizer: http://tinyurl.com/o4b2q95
Policy-based article on composting toilets by The Guardian: http://tinyurl.com/ost5fko


text:
Pink mini fabric bunting, garland with twine
Sweet mini hearts roughly 4 ft long, each little heart is 3" tall, filled with stuffing and threaded with twine, the hearts can slide along the twine if you prefer them closer together or further apart
Shipping & delivery
This item will be posted to you by Patchwork within 3 days of receiving payment.
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Adult's Disney® Mrs. Incredible Costume
Item # WX2-193567
- Details & Specs
Adult's Disney® Mrs. Incredible Costume. Have no fear...
... Elastigirl is here to save your Halloween from "blah" costumes! When it comes to dressing up for Halloween, why let kids have all the fun? It may be taken straight from a Disney® movie, but this superhero set-up is made for young-at-heart grown ups.
Includes the tell-tale red, black and yellow jumpsuit, orange belt, plus the eye mask. Fits like a women's 12-14. Made from 100% polyester. Hand wash cold / line dry. Cool iron if necessary. Shoes not included. Imported.
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from Will Caldwell
71-year-old man beat up walking home from R & R Grocery in Newark. Photographer/Editor: Will Caldwell. Reporter/Writer: Rick W. Holmes.
NEWARK - Newark police are searching for the suspects responsible for beating a 71-year-old man on Thursday afternoon. Authorities say the victim was on his way home from R & R Grocery on South 14th Avenue when he was ambushed by the group. Surveillance video shows the suspects approached him from different angles and eventually met him about a half-block down the street. They kicked him profusely before making off with his gold chain. The victim says this incident marks the second time he's been mugged in the past month.


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Which Joe gave his name to 'sloppy joes'? We look at five interesting sandwiches and their lexical origins.
Color-blindness resulting from insensitivity to green light, causing confusion of greens, reds, and yellows.
Compare with protanopia- 'But it's important to remember that a measurable percentage of men have red-green colorblindness (deuteranopia); instructing them to click the green box for yes or the red box for no, for example, should be avoided.'
- 'Here's a handy list: primary atypical pneumonia, humectant, lapis lazuli, magniloquent, magnetohydrodynamic, deuteranopia, bryology, vorlage, Wesleyan.'
- 'Red-green deficiency (deuteranopia) is the most frequently diagnosed deficiency.'
- 'The genetic cause has been determined for several color vision defects, achromatopsia (the loss of all color vision), blue monochromatism, protanopia, deuteranopia, and enhanced S-cone syndrome.'
Early 20th century: from deutero- 'second'(the colour green being regarded as the second component of colour vision) + an- + -opia.
Further reading
6 punctuation marks you might be using incorrectly
Read moreWe take a look at several popular, though confusing, punctuation marks.
An A-Z of country name origins
Read moreFrom Afghanistan to Zimbabwe, discover surprising and intriguing language facts from around the globe.


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Coins (0) |
Iran 250 Rials 1993 to Date
What a pretty coin. I'd like to add a dazzling uncirculated specimen to my collection. It is a 250 rial coin from Iran, and it is worth face value. The date and denomination uses Easter Arabic numerals.
Coin: 11924
, Genre: Islamic Hindu Buddhist
Requested by: ami, Sat, 21-Jul-2012 17:36:48 GMT Answered by: Paul, Sat, 31-May-2014 16:03:05 GMT Reviewed by CoinQuest. Appraisal ok., Thu, 21-Jul-2016 15:06:56 GMT Requester description: This appears to be a bi-metal coin. It is silver colored in the middle with a gold colored trim. There is little writing on it, but the writing looks like caligraphy. There is a single flower on the other side. It looks like a lotus, but I am not sure. There is a wreath on both sides in the gold trim.
Tags: iran 250 rials rial persian persia iranian silver gold caligraphy monogram single flower lotus am wreath feinsilber sliver siver argent silber silverish silb au goldish golden goldenen script inscription letter monograms initial scripts initals calligraphy letters inscriptions lettering scrip lettered initials florets blossom fler fleurs lises petals leis lisse flowerettes flur stems trefoils floral lily petels orchid lis posy bouquet flowers flour orcid bud lilly fleur lei petal bloomed trefoil floret floer stem flowery lilys fluer fleures pedals wreathed rief reif reef wreathe wreat garland wreth wreah wreaths
Coins (0) |


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Includes digital copy + 1 print.
Each additional print is $3.99
A Fake Dime
Composed by Traditional - Digital Guitar Tab
Product Information
A Fake Dime composed by Traditional - Digital Guitar TabA Fake Dime digital guitar tab. Contains printable guitar tab plus an interactive, downloadable digital guitar tab file.
- This product is available worldwide
The Arrangement Details Tab gives you detailed information about this particular arrangement of A Fake Dime - not necessarily the song.
Not the arrangement you were looking for? View All Arrangements
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Publishing administered by: Mel Bay Publications, Inc.


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Alas, it was Ravens kicker Billy Cundiff being carried off the field after kicking the game-winning three-pointer in overtime.
It was Lindell's eighteenth field goal of 50 yard or more in his 11-year career. Fellow WSU alum Jason Hanson holds the all-time NFL record with 42 career three-pointers from 50 yards and beyond.
ONE WEEK after officially being demoted, Atlanta safety Erik Coleman was facing a Sunday in the unfamiliar role of special teams player, but a first quarter injury to Thomas DeCoud brought him back to the Falcons' first unit defense.
Coleman finished second among Atlanta defenders with nine total tackles.
Here's how the NFL Cougs performed in week seven :
Hamza Abdullah, S, Arizona, 6th season: Declared inactive for the Cardinals' 22-10 loss to Seattle.
Husain Abdullah, S, Minnesota, 3rd season: No recorded stats from the Vikings' 28-24 loss to Green Bay.
Tyron Brackenridge, CB, Jacksonville, 4th season: Posted one solo tackle and one special teams tackle in the Jags' 42-20 fall to Kansas City.
Erik Coleman, S, Atlanta, 7th season: The Spokane native logged eight tackles (7 solo) and a special teams stop in the Falcons' 39-32 win against Cincinnati.
Jed Collins, FB, New Orleans, 2nd season : Did not play; assigned to the Saints' practice squad.
Eric Frampton, S, Minnesota, 4th season: Assisted on one special teams tackle in the Vikings' 28-24 fall to the Packers.
Brandon Gibson, WR, St. Louis, 2nd season: The Puyallup native caught just one pass for 11 yards in the Rams' 18-17 fall to Tampa Bay.
Jason Hanson, K, Detroit, 19th season: Did not play; bye week.
Jerome Harrison, RB, Philadelphia, 5th season: Declared inactive for the Eagles' 37-19 loss to Tennessee. The Ghost is expected to have his coming out party for Philly in two weeks (the Eagles have a bye next week).
Jason Hill, WR, San Francisco, 4th season :Declared inactive for the 49ers' 23-20 loss to Carolina.
Chris Ivory, RB, New Orleans, rookie :: Gained 48 yards on 15 carries in the Saints' 30-17 loss to Cleveland. Cleveland?! Ivory earned Fed-Ex NFL Ground Player of the Week and NFL Rookie of the Week for his performance last weekend.
Rian Lindell, K, Buffalo, 11th season: The Vancouver, Wash. native was perfect on two field goal attempts (long of 50) and 4 extra-point tries in the Bills' 37-34 loss to Baltimore.
Karl Paymah, DB, Houston, 6th season :Did not play; bye week.
Ropati Pitoitua, DE, New York Jets, 2nd season: Did not play; out for the season on injured reserve (achilles).
Marcus Trufant, DB, Seattle, 8th season: The Tacoma native recorded four solo tackles in the Seahawks' 22-10 victory against Arizona. He also forced—and recovered—a fumble.


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Web site designers WebGenius
"Much-needed reference serves as your best source for up-to-date, organized information on stress fractures"
Stress Fractures Editors: Peter Bruker, Kim Bennell, Gordon Matheson
Publisher:Blackwell Science Inc; 1st edition (1999); 190 pages
Back to podiatry books list
Stress Fractures is a much-needed reference serves as your best source for up-to-date, organized information on stress fractures. Written by three leading authorities in this area, Stress Fractures covers the pathophysiology, epidemiology, risk factors, and treatment associated with these injuries.
The reference provides both theory about development of stress fractures and practical management of the various types and sites of stress fractures. It is an essential reference for all clinicians involved in the diagnosis, prescription, and management of these injuries.
Authors Peter Brukner, Kim Bennell, and Gordon Matheson draw together their extensive knowledge base and expertise to provide current and comprehensive information about the subject.
The pathophysiology and epidemiology of stress fractures are covered in the first two chapters. A general overview of diagnosis and treatment of stress fractures is provided in the following two chapters. In the concluding chapters, the management of specific stress fractures is described in detail for the upper limb, the trunk, the pelvis and thigh, the lower leg, and the foot and ankle.
Recent advances in nuclear isotope scans, CT scans, and MRI have enabled stress fractures to be detected and identified much more easily. Stress Fractures pulls together the important information on the topic and offers a valuable, practical guide to risk factors and treatment options for this increasingly prevalent type of injury.
Chapter 1. The pathophysiology of stress fractures. Chapter 2. The epidemiology of stress fractures. Chapter 3. The risk factors for stress fractures. Chapter 4. Diagnosis of stress fractures. Chapter 5. Treatment of stress fractures. Chapter 6. Stress fractures of the uppper limb. Chapter 7. Stress fractures of the trunk. Chapter 8. Stress fractures of the pelvis and thigh. Chapter 9. Stress fractures of the lower leg. Chapter 10. Stress fractures of the foot and ankle.
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Secure purchase Stress Fractures here in conjunction with
Click on your flag to order:
How safe is buying online? It is safer to pay online than it is to give your credit card to a waiter at a restaurant. ePodiatry's partners use encryption technology to convert your personal account details into a secret code which is sent over the internet. Anyone trying to crack the code is looking for a 1 in 1,099,511,627,766 combination! ePodiatry does not have access to your personal information from our partners.
Amazon.com is based in USA, Canada, UK, Germany, France and Japan. They offer an excellent level of service and reasonable shipping charges to clients in countries outside of these (especially Australia, New Zealand and South Africa).
In addition, ePodiatry offers a guarantee of a full refund if not satisfied when Stress Fractures is ordered when clicking on one of the flags above to place your order.
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To celebrate Kentucky's rich historical heritage, and to help create awareness about Native American people in our Commonwealth, a special five-week canoe trip is being planned for early July. This unique river journey is endorsed by the Kentucky Native American Heritage Commission and several Native American veterans and cultural organizations.
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Equip your RENAULT with a set of Rhino-Rack roof racks for work, leisure or anything in between.
Our roof racks are good looking, tough and practical, and feature a range of equipment carriers, trays, ladder carriers, bike carriers, kayak carriers and luggage boxes for RENAULT models.
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"It's Your World" Book Talk
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Welcome to Mill Valley Middle School! We encourage you to subscribe to MVMS communications and receive the PTSA Newsletter and important communications from the school administration.
Please check here for District Policies.
Don't forget to order your yearbook
Connect with the city of Mill Valley, and outsmart the traffic!
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Just when it seemed that it was time to shake off those winter blues, mother nature gave us a late winter surprise.
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The Greens Fee & Cart Rental Discount Plans for the upcoming 2017 golf season, are now available!!
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RSL is dedicated to the goals of operating with integrity, safety & continuous improvement, manufacturing quality by design energy efficient products for residential entryways, and maintaining teamwork among our employees, suppliers & customers.
From its earliest days to the present, RSL has had two primary strategies for success. The first is a focus on quality by design. RSL developed a manufacturing process that makes our doorglass, sidelights and transoms the best in our industry. All of our products have a lifetime warranty on both frames and glass. We ensure that our frames are maintenance free and do not require painting or staining; our insulated blinds, decorative doorglass, and energy efficient commodity doorglass are also guaranteed for exceptional reliability and are thermally sealed for a lifetime of use. Our production team takes enormous pride in maintaining this unrivaled quality by design and treat each product as if it was being made for use in their own home.
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