Indication For Patent Covered Drug Substances Biology Essay

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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 88 000 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 20 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 5 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 6 months

Extension of the market exclusivity period for 2 years


8 years of

data protection


2 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 31 initial marketing authorisations with a paediatric indication were granted, 39 newly authorised paediatric indications for already authorised medicines were granted and 15 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 5 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 7-9 % of trials in 2007 to around 12 % 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 100 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 60 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 20 days. Proposed or requested modifications from NCA should be implemented within 35 days. The Ethics Committees must approve or disapprove these substantial amendments within 20 days. Additional sites can only be included if the Ethics Committee in charge gives approval (within 20, max. 35 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 15 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 7 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 15 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 90 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 10 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 10 years, the subject-identification-list for 15 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

(2008/C 243/01)

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 E 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