The Case of the Missing Minute: Book 1 (4th Dimension Detective Agency)

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Submission at the time of the response to list of questions day for the initial application. It should be noted that multiple applications are subject to a full validation as they are stand-alone applications. Therefore, the validation outcome may differ from the one of the original application. Following the positive outcome of the validation, the evaluation of the multiple application s will be aligned with that of the ongoing initial application, in case the above timeframes have been duly observed by the applicant. The submission of the multiple application s should be done in advance, to allow sufficient time for the validation to be completed by D or D of the ongoing initial application.

The validation period between submission date and start date is 13 EMA working days. Please observe the EMA procedural timetables. Relevant aspects of the Paediatric legislation should be considered as appropriate for each of the multiple applications submitted. The Risk Management Plans for multiple applications should be product specific and reflect the particulars of each specific application e.

Multiple applications can also be submitted after the Commission Decision on the initial application as stand-alone applications or Informed Consent applications. Again, requirements for eligibility and Rapporteur assignment remain. However, as a rule, an abridged timetable for assessment will be adopted in line with a 60 days procedure. Submission of the application s should be done in advance to allow the completion of the validation before the intended start date of the procedure. Combination packs are to be understood as a combination of active substances , where the active substances are included in separate pharmaceutical forms which are included in the same package and are covered by a single marketing authorisation.

Fixed combinations and combinations packs are not synonymous concepts. They will be considered on a case-by-case basis. The applicant will have to justify that the marketing of such a combination of active substances in the same package is needed for indispensable public health reasons.

Applicants are advised to consult the EMA on the acceptability of the proposed combination pack at an early stage of the development in view of their acceptability only in very exceptional circumstances. In any case, the acceptability of the combination pack should be confirmed before the request for eligibility to the centralised procedure and the submission of the Marketing Authorisation Application. Combination pack requests can be submitted to the EMA using the following email address: combinationpacks ema.

The EMA will endeavour to issue an outcome on the acceptability of the combination pack within 60 days. When the acceptability of the combination pack is accompanied by additional questions on the overall development of the product, these can be submitted together with the Scientific Advice questions. The EMA will endeavour to provide a reply on the acceptability of the combination pack within the Scientific Advice outcome letter.

For scientific advice requests, please consult the scientific advice and protocol assistance section on the EMA webpage. A marketing authorisation granted under the centralised procedure is valid for the entire Union market, which means the medicinal product , may be put on the market in all member states. Medicinal products under the mandatory scope belong to one of the following categories:. Advanced therapy medicinal products , other than tissue engineered products, which were legally on the Union market in accordance with national or Union legislation on 30 December , shall comply with this Regulation no later than 30 December Tissue engineered products which were legally on the Union market in accordance with national or Union legislation on 30 December shall comply with this Regulation no later than 30 December For medicinal products falling under the optional scope, applications for the following categories may, at the request of the applicant, be accepted for assessment under the centralised procedure :.

A new chemical, biological or radiopharmaceutical active substance , as defined in Annex III to Chapter 1 of the Notice to Applicants, includes:. Marketing Authorisation application including paediatric indication s for a medicinal product which is not authorised in the Union Article A marketing authorisation application for a medicinal product not authorised in the Union on the date of entry into force of the Paediatric Regulation 26 July and which includes one or more paediatric indication s on the basis of studies conducted in compliance with an agreed paediatric investigation plan PIP.

In all cases listed above, the eligibility of a medicinal product for evaluation via the centralised procedure must be requested by the applicant by submitting a Pre-submission request form Eligibility to: CPeligibility ema. Regardless of whether the product falls into the mandatory or optional scope, or would have "automatic access" or access in accordance with the Paediatric or Advanced Therapy Regulation, an ' eligibility request ' should always be submitted using the specific form and accompanied by a justification of eligibility for evaluation under the centralised procedure.

The applicant should clearly address the specific criterion fulfilled by the product to be eligible for the centralised procedure. See: Question 1 "Is my medicinal product eligible for evaluation under the Centralised Procedure? When submitting a request, the applicant should use the Pre-submission request form Eligibility and send it electronically to: CPeligibility ema. The European Medicines Agency recommends providing the eligibility request preferably, at the earliest, 18 months before submission of the marketing authorisation application MAA and, at the latest, 7 months before the MAA is filed with the European Medicines Agency, at which point it could be submitted as part of the "letter of intent to submit".

For Eligibility requests submitted as part of the "letter of intent to submit", Rapporteurs will be automatically appointed following the confirmation of the eligibility to the centralised procedure provided that the planned submission date is within months. The eligibility request and supporting documentation should be submitted to the European Medicines Agency 10 calendar days before the CHMP meeting, see: Question 3, "What are the dates for submission of eligibility requests?

NB: Review of eligibility applications made under Article 3 2 b will take place over 2 consequent CHMP meetings because of the need to appoint a sponsor s to assess the request. Deadlines for submission of eligibility requests and dates of CHMP meetings, as follows:. Therefore you will not receive a formal response to your request until the following month.

For any scientific evaluation in respect of a procedure, a Rapporteur , and if relevant a Co-Rapporteur , shall be appointed from amongst the members of the Committee for Medicinal Products for Human Use CHMP and alternate members. In addition, for activities covering all aspects of the risk management of the use of human medicinal products , a Rapporteur , and if relevant a Co-Rapporteur , shall be appointed from amongst the members of the Pharmacovigilance Risk Assessment Committee PRAC and alternate members. The pre-submission request form can be accompanied by a cover letter.

We advise applicants to notify the EMA of their intent to submit and request assignment of Co- Rapporteurs 7 months prior to the intended submission date. Although applicants may submit the letter of intent earlier than 7 months prior to the intended submission date, the Co- Rapporteurs appointment procedure will not be initiated prior to that date. Intended MAA submission dates must be as realistic and accurate as possible as such information is crucial to the EMA and to the future appointed Co- Rapporteurs and their assessment teams for planning purposes. The Co- Rapporteurs appointment procedure takes one month and applicants are notified about the outcome.

It is the responsibility of the applicant to liaise with the EMA in due course to confirm its intended submission date and request Co- Rapporteurs appointment. Please be aware that separate pre-submission forms have to be submitted for requesting eligibility and the appointment of Co- Rapporteurs selecting the corresponding indents on the first page of the pre-submission form , even if an applicant submits both requests in parallel.

Due to the particularities of non-prescription medicinal products e. These Rapporteurs will coordinate the evaluation for the duration of the re-examination procedure only. The notified body is requested to submit the letter of intent at least 6 months before the expected date of submission. In the same way as it is important for applicants to plan their application strategies for an efficient use of their resources, it is important for the European Medicines Agency, Committee members and Experts to be able to plan and allocate their workload efficiently.

If the actual submission date is several months after the date originally indicated, Co- Rapporteurs may find it difficult to provide the necessary expertise and re-appointment could be necessary. The European Medicines Agency advises applicants to consider the date of submission very carefully and to notify the Agency and Co- Rapporteurs of a 'real' submission date.

At least seven months before submission, applicants should notify the European Medicines Agency of their intention to submit a MAA and provide the intended date of submission. This should be done by using the Pre-submission request form Pre-submission request form Intent to submit MA , selecting as a scope of request: Centralised Procedure -Intent to submit a MAA ; this should be sent electronically to pa-bus ema.

The appointment procedure for Co- Rapporteurs will be initiated 7 months prior to the Marketing Authorisation Application intended submission date see question 2. Furthermore applicants are requested to re-confirm the submission date months prior to the initially communicated intended submission date, by sending an email to the appointed Product Lead at the EMA. Applicants are finally requested, if they no longer wish to pursue the submission of their application, to notify the European Medicines Agency of their intention to withdraw the request for submission of a MAA.

This should be done by using the pre-submission request form , selecting as a scope of request: Withdrawal of request ; this should be sent electronically to pa-bus ema. Please note that this will close the case procedure and the whole pre-submission history. The submission deadlines and full procedural detailed timetables are published as a generic calendar see submission deadlines and full procedural timetables. Applicants should ensure that a technically valid eCTD submission is received by the EMA before the submission deadline.

Any technically invalid sequence will result in non-acceptance that may cause a delay in the start of the procedure. After the notification of a valid application, the Agency will charge the appropriate fee. For more information regarding the applicable fee, see question "What fee do I have to pay and how is the appropriate fee for my application calculated? For more information on the complete set of documents that need to be submitted and for the addresses of Committee members for submission of the application, see question " How and to whom shall I submit my dossier?

In case the previously indicated submission date of an upcoming application for marketing authorisation is changed, the applicant shall inform the EMA by re-sending to pa-bus ema. The text of the e-mail should also describe the type of the change requested. The change in intended MAA submission date must be notified as soon as possible. Since this information is crucial to the EMA and to the appointed Co- Rapporteurs and their assessment teams for planning purposes the intended submission date should be accurate and realistic.

In some cases, a change in the planned submission data could lead to re-appointment of one or several Rapporteurs , if the previously appointed Rapporteur s will not be able to perform the assessment according to the new timings.


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In such case the applicants will be informed accordingly. Applicants requesting an accelerated assessment procedure should justify that the medicinal product is expected to be of major public health interest. Based on the request, the justifications presented, and the recommendations of the Rapporteurs , the CHMP will formulate a decision. Such a decision will be taken without prejudice to the CHMP opinion positive or negative on the granting of a marketing authorisation. Applicants are reminded that evidence requirements for applications to be assessed under accelerated assessment are the same as for other applications.

If the CHMP accepts the request, the timeframe for the evaluation will be reduced to days. The applicants will be allowed to have one month clock-stop by default for preparation of responses to Day 90 List of Questions and no clock stop by default after Day List of Outstanding Issues. Request for an accelerated assessment : timing and justification. Before the submission of a potential request for accelerated assessment , applicants should seek guidance from the Product Lead to ensure timely submission of their request.

It is strongly recommended that applicants request a pre-submission meeting six to seven months before submission to prepare for evaluation under accelerated assessment. In this meeting, they can discuss their proposal for accelerated assessment with rapporteurs from the CHMP , the PRAC and CAT in case of an advanced therapy medicinal product and the EMA and present the data package and risk management plan they intend to include in their application. Any request for accelerated assessment should be made as early as possible before the actual submission of the marketing authorisation application and at least months before the actual submission.

Applicants requesting an accelerated assessment procedure should duly substantiate the request and in particular, justify their expectation that the medicinal product is of major public health interest particularly from the point of view of therapeutic innovation. There is no single definition of what constitutes major public health interest. This should be justified by the applicant on a case-by-case basis. The justification should include the major benefits expected and present the arguments to support the claim that the medicinal product introduces new methods of therapy or improves on existing methods, thereby addressing to a significant extent the greater unmet needs for maintaining and improving public health.

The key items to be described in the justification, and the appropriate level of detail, should be evaluated on a case-by-case basis. The request should be presented as a short but comprehensive document ideal length pages. In order to better anticipate and integrate routine GCP and pre-approval GMP inspections into the accelerated assessment procedure the applicants should provide with their request for an accelerated assessment also the following information using the published templates that should be accurate, complete and reflect the content of the application dossier that will be submitted:.

Concerning GMP aspects template to be used. Applicants are also advised to include this as a topic for discussion in the pre-submission meeting with the EMA. Concerning GCP aspects template to be used. The Applicant should provide the list of all the pivotal clinical studies protocol number and title and for each pivotal study:. In case a need for an inspection is identified, the inspection will be requested as early as possible in the evaluation procedure in order to accommodate the inspection within the accelerated timetable please refer also to questions 5.

When submitting an accelerated assessment request, the applicant should use the templates for:. Following receipt of the request, the Rapporteurs will produce a briefing note including the Rapporteurs ' recommendations as to the appropriateness of an accelerated assessment. The CHMP will consider the request submitted by the applicant, the Rapporteurs ' recommendations and the views of other CHMP members, in order to conclude on the acceptability or not of the request. If necessary, the CHMP may request clarifications from the applicant about the request. The reasons for accepting or rejecting the request will also be summarised in the CHMP assessment report.

The pre-submission meetings represent important points in the product development and regulatory approval process, and relate to the preparatory steps in advance of submitting a request for marketing authorisation application MAA. Successful follow up of the advice given in pre-submission meetings should enable applicants to submit applications, which are in conformity with the legal and regulatory requirements and which can be smoothly evaluated.

These meetings will also enable applicants to establish contact with the EMA Product Team Members who will be closely involved in the centralised evaluation procedure of their medicinal product. MAA pre-submission meetings are aimed at providing applicants with information that will assist them in the finalisation of their upcoming marketing authorisation application.

Such meetings typically address product-specific legal, regulatory and scientific issues in order to facilitate subsequent validation and assessment of the application. However, experience has shown the usefulness of pre-submission meetings even for applicants who already have experience with the centralised procedure , to address issues specific to their upcoming application in view of the constantly evolving regulatory framework and its application. The PSG addresses a number of questions, which users of the centralised procedure may have, together with hyperlinks to relevant legislative documents and procedural guidelines which further complement the advice given in the PSG.

As EMA commits to keeping the pre-submission guidance document updated, there should not be a need to check or confirm the answers given in the PSG document at the time of the pre-submission meeting. Other topics not listed in the form may be added. Pre-submission meetings for marketing authorisation applications MAA usually take place months before the intended submission date.

It is recommended to send the Letter of Intent ahead of the meeting request, in order to avoid any delay in the meeting date as a result of the time needed to appoint the Rapporteurs and the EMA product team. Please also note that during the period when the Agency is relocating to the Netherlands until its establishment in the permanent premises, for logistic reasons pre-submission meetings will only be held remotely at designated specific dates.

Applicants may indicate their preference for a date in the pre-submission request form, which will be taken into account by EMA when allocating the exact date and time for the meeting. The meeting will start with the applicant's ' presentation followed by a discussion on the presentation and the topics ticked in the pre-submission request form. The total meeting duration should not exceed 2 hours.

Please note that the PM will be chairing the meeting and will remain the primary contact point between the applicant and the rapporteurs during the procedure. Note : Applicants must in all cases comply with all requirements of Union Legislation. Provisions, which extend to EEA countries i. For request received as of 1 October , pre-submission meetings are being held remotely preferably via teleconference, or video-conference.

On the basis of the information provided, EMA participants will discuss with the applicant the appropriateness of the chosen legal basis in view of the available data, highlight elements to be specifically addressed in the CTD Overviews e. EMA may also draw attention to relevant scientific and regulatory guidelines , in particular the CHMP 'clock-stop' rules in case of a potential premature submission, recommend further scientific advice and suggest improvements to the product information. The topics listed in the pre-submission meeting request form are grouped according to the following areas:.

It is envisaged that the issues will be addressed in this order at the pre-submission meeting. This will allow a sequential discussion of all the applicant's questions on topics related to the same area, with involvement of relevant EMA staff with expertise in the area concerned e. Labelling review and standards staff members will attend the discussion on the topics dealing with product information and transparency etc.

Note: Applicants wishing to meet with their appointed Co- Rapporteur and assessment teams at national level should also inform the Product Lead so that relevant EMA staff from the Product Team could participate in such a meeting via teleconference. In any case, minutes of such meetings should be provided to the Product Lead. Detailed meeting minutes should be prepared by the applicant and provided to the Product Lead within 2 weeks after the meeting. EMA Product Team Members will subsequently review the minutes within 2 weeks and agree the final amended minutes with the applicant.

Timelines: Pre-submission meeting request, after submission of Letter of Intent, should be sent 6 weeks in advance of the targeted meeting date. Meeting date should be targeted at months in advance of the proposed intended submission date. Consider to start the whole process, including submission of the Letter of Intent, around months in advance of the intended submission date.

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Although it is not mandatory under Union legislation, in practice, many companies submitting marketing authorisation applications under the Centralised Procedure wish to use invented names for their medicinal products. As part of the EMA's role in evaluating the safety of medicinal products in the centralised procedure , it is obliged to consider whether the invented name proposed for a medicinal product could create a public-health concern or potential safety risks.

In particular, the invented name of a medicinal product :. Other relevant experts e. WHO experts are consulted on a case-by-case basis. The NRG meets 6 times a year approximately every 2 months. Its conclusions are presented for adoption at the subsequent CHMP plenary meeting. Provided that the medicinal product is eligible for evaluation under the Centralised Procedure , the applicant should inform the EMA of the proposed invented name s for their medicinal product at the earliest 18 months and preferably months prior to the planned submission date of the marketing authorisation application.

See also Question 4a. What are the dates for submission of invented name requests for the deadlines for submission of Proposed Invented Names. Applicants may submit a name review request after eligibility has been confirmed by the CHMP or in parallel to the eligibility request. Applicants are advised to contact the NRG secretariat prior to submission of the name review request form for advice if eligibility is not yet confirmed at that time.

An electronic request form in PdF format has been developed and replaces the current form in Word format. Up to two invented names can be accepted per Marketing Authorisation Application from which the applicant should select the final name to be used. Up to two newly proposed invented names can be considered at each NRG meeting per Marketing Authorisation Application.

It should be noted that once two invented names have been deemed acceptable by the NRG for a Marketing Authorization Application, no further review of newly proposed names is allowed unless agreed with EMA on duly justified grounds i. Applicants should follow the criteria described in the 'Guideline' when proposing invented names and would be expected to review the proposed invented name, applying the criteria before requesting that an invented name be considered.

Where the applicant deviates from these criteria, justification should be provided. The detailed procedure is described in the 'Guideline'. Applicants may submit justifications for rejected names in addition to the entitlement of 2 invented names reviewed per meeting.

However, only two accepted names can be retained in the NRG database and therefore the applicant should indicate in advance which two names should be retained in case that they are accepted. Change of the invented name after the marketing authorisation is granted. This can be done either in case of a marketing authorisation being granted under INN or common name together with a trademark or the name of the MAH or in case the MAH wants to change the initial invented name.

Such Type IA IN variation is possible provided that the check by the Agency on the acceptability of the new name had been finalised and was positive before implementation of the new name. Taking into account that the MAH will be required to submit the EMA letter of acceptance of the concerned invented name as part of the variation application, it is recommended that the proposed invented name be submitted at least months in advance of the foreseen implementation date and submission of the Type IA IN variation notification.

However, priority may need to be applied on the basis of the urgency of the request. Should the review of a request be postponed, the NRG team will confirm this within 2 weeks of the published submission deadline. Each medicinal product should be placed on the market under a name and in a package suitable to ensure identification and differentiation. The medicinal product should be identified in the product information according to the following rule: the name of the medicinal product should be followed by the strength and the pharmaceutical form. However, when otherwise referring to the medicinal product throughout the product information text, the strength and the pharmaceutical form do not have to be mentioned in the name.

In the SPC, the INN or the common name of the active substance should be used when referring to properties of the active substance s rather than the invented name. The use of pronouns e. Thus, whenever the "name of the medicinal product " is specifically required to be provided in the SPC, labelling on the outer or immediate packaging or on blisters or the Package Leaflet , it should be written in the following order as:. Braille is the internationally widespread reading and writing system for blind and partially sighted people. It consists of arrangements of dots which make up the letters of the alphabet, numbers and punctuation marks.

The revised legislation requires that the name of the medicinal product is expressed in Braille format on the packaging of the medicinal product. In addition, Marketing Authorisation Holders must ensure that the package leaflet is made available on request from patients' organisations in formats appropriate for the blind and partially-sighted.

These new requirements apply to new marketing authorisations with Commission Decisions as of 20 November Nevertheless, companies are encouraged to apply the provision to all centrally authorised medicinal products as soon as possible. The invented name of the medicinal product followed by its strength should be put in Braille on the packaging of the product. The uncontracted Braille system should be used. For medicinal products authorised only in a single strength, it is acceptable that only the invented name in Braille is put on the packaging.

In case where there is no secondary packaging, it is possible to fix an adhesive Braille label around the bottle. On a volunteer basis, the name in Braille can be expressed on all packaging components. It is also possible for companies to include, on a voluntary basis, further information in Braille on bigger volume packages e. In case of multilingual packaging, the name in Braille has to be printed in all the different languages concerned.

It should be noted that there is no need to put the name in Braille on the packaging of products which are only intended for administration by health care professionals. In case of small volume packages up to 10 ml with limited space capacity, alternative means of providing Braille information may be considered, e.

At the time of submission of the application, applicants should address in Module 1 - section 1. In addition, the information that will appear in Braille on the printed outer packaging should be mentioned, if applicable, as normal text in section 16 of the outer packaging labelling Module 1 - section 1. Module 1 — section 1. Package leaflet for blind and partially sighted.

On request from patient's organisations the package leaflet should be provided for partially-sighted people in a suitable print, taking into consideration all aspects determining the readability. For blind people the text has to be provided in an appropriate format, e. Choice of the appropriate medium should be made by the MAH in consultation with representatives of organisations for the blind and partially sighted. Further guidance on the implementation of the requirements for Braille and the requirements for the package leaflet for the blind and partially-sighted is provided in the European Commission ' Guideline on the Readability of the Labelling and Package Leaflet of Medicinal Products for Human Use'.

The mandatory information to be included on the outer packaging of a medicinal product is defined in Article If the applicant proposes to include on the packaging of the medicinal product such additional information, a justification that the above requirements are met should be included in the submission section 1.

A " Mock-up " is a copy of the flat artwork design in full colour, presented so that, following cutting and folding where necessary, it provides a replica of both the outer and immediate packaging, so that the three dimensional presentation of the labelling text is clear. A " Specimen " is a sample of the actual printed outer and immediate packaging materials and package leaflet i. The checking process of mock-ups and specimens in the Centralised Procedure is based on the following general principles:.

Based on the above, EMA will not check the national requirements included in the blue-box. However, the fact that the mock-up has to be a real example of the sales presentation implies that the mock-up should indicate how the information specifically required by Member States such as price, reimbursement, legal status, identification and authenticity will be presented in the 'blue box'. This means that if at the time of submission of the mock-ups this specific information is not yet known, at least an indication should be given of the way in which this information will be printed in the 'blue box' on the outer packaging i.

The inclusion of a national barcode on the labelling would normally be viewed as a Member State driven requirement located within the 'blue box' on the outer carton. However, EMA can also accept the inclusion of a national barcode on the immediate packaging e. The applicant will be informed about the outcome of the check. ATC codes. The Anatomical Therapeutic Chemical ATC classification is a system in which medicinal products are divided into different groups according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties.

The medicinal products are classified in groups at five different levels. The applicant for a marketing authorisation should apply for an ATC code using the application form on international language for drug utilization research. This website also gives information on data to be submitted.

If an ATC code has been assigned, it should be given in section 5. The SmPC should also be amended accordingly. If the ATC code is obtained after opinion, the Agency should be informed and the SmPC should be amended accordingly either as a type-IA variation or at the occasion of another variation after the Commission decision has been obtained. The same procedure applies in cases where a revision of a final ATC code by the WHO for medicinal products already authorised.

International non-proprietary names. An international non-proprietary name INN identifies a pharmaceutical substance or active pharmaceutical ingredient by a unique name that is globally recognised and is public property. The aim of the INN system has been to provide health professionals with a unique and universally available designated name to identify each pharmaceutical substance.

To make INNs universally available, they are formally placed by WHO in the public domain, hence their designation as 'non-proprietary'. The process of INN selection follows three main steps:. If the INN is obtained after opinion, the Agency should be informed and the PI should be amended accordingly either as a type-IA variation or at the occasion of another variation after the Commission decision has been obtained.

For certain biologicals, because of their complexity, general rules for INN are not easily formulated. Some of these substances may have descriptive names assigned by other institutions. These names may not be suitable as INNs. Some nomenclature schemes for groups of biological compounds are provided in INNs for biological and biotechnological substances. For vaccines, the INN is not applicable and in these cases either the pharmacopoeial or common name of the antigens should be used.

In the absence of an INN, the common name or scientific name of the pharmaceutical substance should be used. Samples for testing the proposed medicinal product are not required at time of submission of the application. However, reference to already approved package leaflets may be acceptable where appropriate, based on a sound justification by the applicant. Examples of when this may be considered acceptable as well as the considerations to be taken into account when choosing the types of 'reference' package leaflets are detailed in the Guidance concerning consultations with target patient groups for the package leaflet.

If user consultation has been performed on a package leaflet in the old QRD templates, there is no need to be retested when updating according to the new QRD templates. However, it should be noted that compliance with the QRD templates does not exempt from the obligation to undertake a user test or other form of user consultation. The package leaflet should be legible, clear and easy to read in all EEA languages, but it is normally sufficient to undertake user consultation in one EEA language. However, results of user consultation should be presented in English in order to allow assessment.

One of the possible ways of complying with the new legal requirement is by performing a 'user testing' of the package leaflet , i. It is a development tool which is flexible and aims to identify whether or not the information as presented, conveys the correct messages to those who read it. Testing itself does not improve the quality of the information but it will indicate where there are problem areas which should be rectified.

Other methods than user testing may be acceptable provided that the outcome ensures that the information is legible, clear and easy to use so that patients can locate important information within the package leaflet , understand it and enables the user to act appropriately.

Such alternative methodology will have to be justified by the applicant and will be considered on a case-by-case basis. An example of a method for user testing of a package leaflet is provided in the Annex 2 of Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use. During the pre-submission phase the applicant may discuss how to address 'user consultation' with EMA and Co- Rapporteur , if necessary.

This discussion may indicate whether new 'user consultation' would be necessary or whether a justification for its absence or 'focused' user testing could be acceptable. At the time of submission of the application, information regarding the 'user consultation' performed together with a presentation of its results, or a justification for not performing such consultation, is to be included in Module 1 Section 1.

The presentation of results should be shortened to a summary explaining how the consultation was executed and how the resulting package leaflet accommodated any need for change. The recommended structure of such a summary is provided in the Guidance concerning consultations with target patient groups for the package leaflet.

In their assessment reports, the Co- Rapporteur will include the assessment of the results of user consultation or of the justification for its absence as well as a conclusion on the overall readability of the package leaflet. It should be noted that, if not included in the initial submission, the results of user consultation or any further clarification, as requested, will have to be submitted as part of the answers to the list of questions at Day The user consultation results and the Co- Rapporteur 's assessment will also be forwarded to QRD Group, as useful information when reviewing the draft product information.

Some Holders of Union Marketing Authorisations have requested that there be a contact point identified in the Package Leaflet and on the label. This would normally be the Holder of the Union Marketing Authorisation. However, a Marketing Authorisation Holder may wish to add the name of another local contact point, the "local representative". All telephone numbers should be accessible when dialled from abroad e. Reference to website addresses or to e-mails linking to websites are not allowed, either for the marketing authorisation holder or for the local representative.

Designation of a local representative cannot be a requirement but, when the holder of a Union Marketing Authorisation wishes to identify a local representative in the leaflet, all of the Union must be covered so that the consumer in each Member State and EEA country has equivalent access to a local representative. A local representative may be designated for more than one Member State or EEA country and may also be the MAH when no other local representatives are indicated.

Moreover, in principle, only one local representative should be indicated per Member State or EEA country. Local representatives should be able to address queries in the local official EEA language of the country for which he or she is designated. There has been some confusion with regard to terms such as 'exploitant', 'technical director' and 'distributor'. Since there is neither a commonly agreed understanding of these terms nor an equivalent legal definition of them amongst the Member States, and in the absence of any reference or definition in Union law, reference to such terminology will not be accepted for a medicinal product authorised by the Union.

It must be recalled that Member States may not require that a local representative of the MAH be appointed for their territory. Therefore, the arrangements outlined above are purely optional for holders of Community marketing authorisations. The classification for the supply of the medicinal product to the patient is also referred to as 'Legal Status'. Categories for the Legal Status of a medicinal product.

At the first level, 'main categories', the medicinal product is classified either as:. To this end, the factors laid down in Article 71 paragraphs 2 and 3 should be taken into account. Medicinal products , which meet the criteria for both above-mentioned 'sub-categories', will be subject to special and restricted medical prescription. The definition and therefore also the implementation may vary in those Member States where the 'sub-category' exists. At the pre-submission stage applicants should include a proposed classification for the supply of the medicinal product in their "notification of intention to submit an application" to be sent to the European Medicines Agency at least 7 months before submission.

At the time of the submission of the application applicants should indicate their proposal for Legal Status in the section 2. As regards mock-ups and specimens , the use of any 'sub-category' at national level e. Such symbols or expressions are set out in the Annex to the Guideline on the packaging information of medicinal products for human use authorised by the Union.

The European Medicines Agency strongly advises Applicants to follow this guideline since compliance with the guideline ensures compliance with Union legislation. The data requirements for an application to change the classification for the supply of a medicinal product from to prescription to non-prescription "Switch" are outlined in Part 2 of the Guideline on changing the classification for the supply of a medicinal product for human use. In addition, according to Article 74a of the same Directive, a change of classification may benefit from one year of protection.

This 1-year period of protection covers significant pre-clinical tests or clinical trials carried out for the purpose of substantiating an application for a change of classification. Commission decisions authorising a change of classification will contain a clear statement of whether the change is based on significant pre-clinical tests or clinical trials.

Further information on Legal Status is provided in the Guideline on legal status for the supply to the patient of centrally authorised medicinal products. The ' Guideline on the packaging information of medicinal products for human use authorised by the Union ' defines 'multipacks' as 'packs composed of several single packs of the same strength of a medicinal product.

Thus, it is acceptable to include the term 'multipack' only when it refers to a presentation composed of several single authorised packs of the same strength. The multipack outer carton should display all legally required items including blue box. The inner boxes should not contain the blue box and each individual inner box should contain a package leaflet. Information in Braille, when applicable, should be present on both the outer packaging and inner boxes. The inner boxes should include the mention 'Component of a multipack, can't be sold separately'.

All other relevant statements to include in the product information for a multi pack presentation are described in the QRD product information annotated template i. The Paediatric Regulation places some obligations for the applicant when developing a new medicinal product , in order to ensure that medicines to treat children are subject to ethical research of high quality and are appropriately authorised for use in children, and to improve collection of information on the use of medicines in the various subsets of the paediatric population. The paediatric population is defined as the population between birth and the age of 18 years meaning up to but not including years.

This means that the application will have to include the PIP decision but also the results in accordance with the agreed PIP. This means that the application will have to include the PIP decision including the deferral granted and if applicable, any completed studies. Where results of paediatric studies are submitted, applicants should include in the clinical overview a rationale supporting the proposed changes to the Product Information.

In particular, if the PIP is completed and the results of all studies are available, the applicant should explicitly discuss why the generated data support or do not support the intended paediatric indication s stated in the PIP. However, the following types of application are exempted from the application of the above requirements:. Such compliance check consists of verifying that the fulfilments of the measures as mentioned in the PIP decision including the timelines for the conduct of the studies or collection of the data are fulfilled.

The compliance check procedure is explained in the document Questions and answers on the procedure of paediatric-investigation-plan compliance verification at the European Medicines Agency. Applicants are strongly recommended to apply for the compliance check before submission of the marketing authorisation application to not delay the validation phase. Further details on the format timing and content of PIP or waiver applications as well as on the compliance check can be found in the Commission guideline.

If your medicinal product has been designated as an orphan medicinal product , you will have to consider the following points at the time of submission of your application for marketing authorisation :. When an application for orphan designation is still pending at time of submission of the application for marketing authorisation , it is nevertheless possible for the medicinal product to be authorised as an orphan medicinal product , provided that the orphan designation is granted and confirmed by the COMP before the granting of the marketing authorisation. However, in such cases, the eligibility to the centralised procedure which precedes the submission of the application for marketing authorisation cannot be based on Article 3 1 , Annex 4 — Orphan designated medicinal product.

Similarly, a fee reduction will not be applicable, as it can only be considered if orphan designation has already been granted at the time of submission of the application for marketing authorisation. In advance of submission of your application for marketing authorisation , irrespective of whether your medicinal product has been designated as orphan or not, you are advised to check the Community register of orphan medicinal products , for information on medicinal products designated as orphan which are under market exclusivity protection.

You will have to indicate in the application form section 1. If any of the designated orphan medicinal products has been granted a marketing authorisation in the Union, and a period of market exclusivity is in force, you will have to provide in Module 1. This legal requirement arises from Article 8 1 of the Orphan Regulation which provides that where a marketing authorisation in respect of an orphan medicinal product is granted, the Agency and the Member States shall not, for a period of 10 years, accept another application for a marketing authorisation , or grant a marketing authorisation or accept an application to extend an existing marketing authorisation , for the same therapeutic indication , in respect of a similar medicinal product.

It also defines similar active substance as an identical active substance , or an active substance with the same principal molecular structural features but not necessarily all of the same molecular features and which acts via the same mechanism. Based on the above mentioned definitions, the assessment of similarity between two medicinal products takes into consideration the following criteria.

If significant differences exist within one or more of these criteria, the two products will not be considered as similar. Please note that if the Agency identifies a possible similarity issue not addressed by the applicant before validation, the applicant will be asked to complete the application with information on similarity and, if applicable, on one of the derogations. Validation of the application will only proceed once the applicant has submitted a report justifying the lack of similarity or, if similar, additional information justifying one of the derogations in Article 8 3.

The flowchart below illustrates the Agency validation of marketing authorisation applications with respect to orphan similarity and derogation. As considerable time may elapse between validation of an application and adoption of an opinion, if applicants become aware of medicinal products which have been authorised as orphans for a condition related to the therapeutic indication proposed in their application, this information should be communicated promptly to their Product Lead at the Agency in order to arrange for the submission of updated application form and modules 1.

In any case, the Agency will check at certain milestones of the procedure, i. Day , Day and prior to adoption of a CHMP opinion whether new orphan medicinal products have been authorised for the same condition. If your product is considered to be similar to any authorised orphan medicinal product , you will have to provide in Module 1.

As considerable time may elapse between validation of an application and adoption of an opinion, if applicants become aware of medicinal products which have been authorised as orphans for a condition related to the therapeutic indication proposed in their application, this information should be communicated promptly to the Product Lead at the Agency in order to arrange for the submission of updated application form and modules 1. The Agency requires the applicant to provide background information in support of the application relating to the manufacture including packaging , batch testing and batch certification batch release by the qualified person in the EEA.

This should be sent to the Agency along with the application dossier. Switzerland is not part of the EEA. Once validated, it is normally not permitted to add a new site or to change the steps of manufacture or batch release described under module 1. Any additional sites or changes in the manufacturing or batch-release arrangements should be submitted as a variation after the granting of the marketing authorisation. The information on manufacturing and batch-release sites submitted in module 1. All the manufacturing and batch-release sites mentioned in module 3 must be listed in module 1.

All sites involved in the production of the finished medicinal product and of the active substance must be described name and detailed address, including building reference in module 1. I tried to focus. Maybe, just maybe, if this actually was some big, stupid, fainty dream, if I solved my murder, Id wake up. Like, it was a coma and not a dream. Ohmigod, if I was in a coma my. And she was going to know I stole her boots. So this Other Side, I said, trying to stay calm. If we figure out who killed me, how do I get there? Through the Big Red Door, said a new voice behind me. I spun around to see a brunette standing in the doorway.

She was not channeling Nancys reassuring smile or the kindness in Lornas eyes. Instead she looked bored. As if shed been here a million times before and couldnt care less. I wondered how long shed been standing there, just listening. Thats Tess, Lorna said, checking out her cuticles. Shes been here the longest of all of us girls. Tess is the best, but she can be kind of Nancy shot Lorna another look and gave me an eye roll.

Subtle, Lorna. I can be kind of what? Tess asked. A megabitch? When Lorna shrugged vacantly, Tess turned to me. Well, seeing as I appear to have a rep, I may as well live up to it. All those little fantasies youre currently having? The ones where youre trying to convince yourself that this isnt real and any second now, Mommy dearest will come into your bedroom and wake you up? Forget them. Theyre all lies. She carried on talking before I could tell her Id already worked out I was in a coma.

These twoshe paused to gesture toward Lorna and. Nancytheyre all, Lets make it easy for newbies, let them come to terms with it in their own time. Well, that tactic didnt help me. In fact, nothing helped me. So heres the truth: Youre dead. End of story. The only thing you can do is deal with it and hope youre lucky enough to move on.

See a Problem?

Tess gave me a look that practically screamed capisce? Outside a cab horn honked. Got to say it, Lorna said eventually. That girl has a way with words. Youre totally dead, Charlotte. And thats when I tried to throw up. Except I couldnt throw up anymore. I couldnt do much of anything anymore. My head was swimming. I wasnt sure if it was the having-justdied part or the its-impossible-to-take-in-all-this-information part of the situation that was freaking me out the most; but on reflection, I guess it was probably the part where I was dead.

That morning all I had to worry about was where to meet David for lunch, whether Id get tickets for the portrait exhibit at the Met, and what Dad was going to say when he heard Id flunked chemistry. As in, didnt like me so much that they decided to murder me. What about my poor parents, did they even know yet? And David? Did this mean wed broken up? Tears welled at the corners of my eyes. I tried my hardest not to think about the Living, as Nancy had called them. Come on, Charlotte, I told myself, biting down on my lip and waiting for it to hurt.

But it didnt. Hold it together. There must be a way to fix this. I better show you the Door, Nancy said, all businesslike again, desperately trying to distract me. I know its a lot to take in, but we have to get moving. Every second we waste could mean we miss out on a vital clue to what happened to you and we cant have that, or well never find your Key. My what? I asked, pressing my finger to my lip.

No blood. Your Key, Lorna said. Dont worry, its taken me four years to understand all this stuff. Its more complicated than applying a streak-free fake tan! I followed Lorna and Nancy out of the room. My new room. For that moment, at least. One thing was for sure: dead or not, I wasnt ready to leave my life behind just yet. But honestly? Id seen more impressive entrances to clubs on the Lower East Side.


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  6. This, said Nancy, with all the drama someone under five foot five could muster, is it: the Big Red Door. I politely pretended to take a moment to admire it Mom didnt raise me that badly , but in truth? Sure, I heard her when she said that, if we were going to find my murderer, we didnt have time to waste, but I was too thrown to take it in. What felt like seconds ago I was standing on the subway platform. Now I was expected to be all breezy about my death and impressed by a door that might take me to some Other Side. Um, wow? I finally managed.

    You didnt have to be a Mensa member to see how the entrance to the Other Side got its name. It was big say, one story tall , red wood, in case those kind of details interest you , and a door. Though it was hard to check off the last point, seeing as it was firmly shut. And apparently staying that way until I solved my murder and found my Key.

    Whatever that meant. Big Red satalmost hiddenin an unassuming alcove just off Hotel Attesas main lobby. So this was what my way out of this nightmare looked like. So far, so unhelpful. Run me through how it works again. I turned to Nancy and tried to look super-interested.

    Maybe the sooner I got the hang of things, the sooner Id feel less Well, where shall I start? Whether she sensed my bewildered horror or not, Nancy was clearly loving this part of her job. Rule One: The Door can only be opened by a ghosts personal Key. So, when we solve your murder She smiled as if that was a sure thinglike getting your period on the day of an important swim meet or your cell battery dying just as the guy you like finally calls. Youll get your Key, put it in the door andwhoosh!

    Just the sort of noise I imagined the entrance to the next world making. Finally Nancy sensed my lack of okay. We have no idea how long its been here, she said, desperately. It could have been around for hundreds or thousands of years in some form or other. After all, kids must have been murdered in New York ever since time began. Nancy took a second. I got the impression that, for once, there was something she hadnt thought through. Well, definitely since the Dutch rocked up anyway. Or the Native Americans. Or the. Or maybe even years and years before that, Nancy finished unconvincingly.

    Now she was giving me a history lesson. This was getting more and more surreal. Though getting pushed under a T. She was examining the ends of her hair like a pathologist from CSI. I bet she massively regretted not booking a pre-death spa day. Imagine spending eternity with split ends or an imperfect manicure.

    How did she end up here? Someone spike her Mac lip gloss with cyanide? Lets start with the basics, Nancy said. Rule Two: In the Attesa, things work in pretty much the same way as they did when you were alivegive or take a few little changes.

    From the back pocket of her pristine, pressed jeans, she produced an equally pristine, pressed booklet with The Rules typed on its front cover. It was about as thick as the length of a thumbnail. Nancy handed the book to me, way too eagerly for someone about to talk about my death. Everything is covered in here she smiled encouraginglybut obviously its my job to talk you through things too. Lorna groaned. As the Attesa exists inwhat we assume to bea kind of limbo, you interact with everything in here as you did when you were Living.

    I looked at Nancy blankly. Nancy sighed. I wasnt catching on as fast as shed hoped. In other words, in here, you act like you did when you were alive. So you can open this curtain, use the elevator, move these pieces of paper. She ruffled some stuff on the table in front of the Door for effect. Of course, as youre a ghost now and formed of a ball of kinetic energy rather than cells, you can walk through the walls if you really want to.

    She put her hand clear through the white plaster to my left. But thats just showing off. Oh, and before you ask, no, you cant fly. That would be stupid. Of course. On to Rule Three: Like I said before, the Attesa is protected, which means the Living cant see it or us when were in it. When were outside, in the human world, the Living cant see or hear us unless we want them to. Wait a secondthe Living could see us if we wanted them to?

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    This sounded interesting. But well get on to that later. Right now, what I really want you to see is HHQ. H-H- what? Nancy led us out of Big Reds alcove and pulled aside a velvet curtain to the left of the reception desk. Behind it was. I followed her down them, Lorna and her perfectly respectable split ends trailing behind, to a badly lit corridor below. From what I could see it was dark, dingy, like the areas of any hotel that guests werent meant to see.

    Clearly the glamour of the Attesa didnt extend to the lower floors. Why were we here? At the end of the corridor was a regular-size door. Above it was a cardboard sign with HHQ written in very neat, deliberate letters. Whoever made that sign had probably practiced writing the letters over and over to make sure they were perfect. That said, the signs effect was slightly ruined by being placed over the doors original, professional hotel sign. The first and last letters an O and an E peeked out behind the cardboard.

    I decided the original sign had probably spelled out Office. Now this, said Nancy, opening the door, this is the heart of our operation: HHQ. She swung the half-wood, half-frosted-window door open a couple of feet and I squinted inside. The room was about twelve by twelve feet in size. More than enough to swing a jackrabbit, as my grandmother would have said, but certainly not as big as Id expected from an HHQ. Whatever that was. Nancy walked inside and beckoned for me to join her. Three oblong windows spanned the top third of the facing wall.

    Through them, I saw a pair of feet walk past. I realized that, having come downstairs, those windows must be at street level with the road. And, from down here, you could see peoples shoes as they walked by. It was so weird seeing themMr. Nike, Ms. Stiletto, oh and hello, Mr. I looked at the passing feet and wondered, Had I walked past the Attesa before?

    I must have. After all, there was that amazing boutique at the end of the street that always had great sales. And that basement dive bar where they never asked for ID. Even when Davids mom had just made him get a haircut and he looked, like, two years younger than the week before. Had some newly dead girl stared up at my sneakers as I stomped past? Wondering what kind of person stood in them? Had she thought how much easier everything had been before? Before some idiot stole her future away and she ended up in this place, trying to solve her own murder. I sighed and looked around the room properly.

    On the wall to the left of the windows was a map. A massive map of Manhattan. I leaned in more closely. Someone had drawn sharks in the Hudson um, not cute and put a pin in a spot labeled School on East 49th Street and Madison Avenue. Another on West 71st labeled Home. And another Hey, wait a minute! That was my school and my home and most definitely my murder scene. This map was all about me. I swallowed, even though I had nothing to gulp down. School, my apartment, the subway But murder scene? Seeing it written out like that was so Someone had carefully tagged this map with all the places Id visited on my last daywas that still today?

    And Id bet my afterlife that I knew who that was. Um, Nancy, not to sound all drama queen when weve only just met, but this map? Its all about me. I know it is. And it is freaking me out. What gives? Nancy took a step to her leftto reveal a large blackboard behind her, opposite the map wall. Oh, great, so we were back in school. Then I read what was on it. Cause of death: Accidental. Will someone please tell me what is going on? I heard myself say. Okay, Charlotte, sit. Nancy patted a chair beside her.

    The Art of Storytelling and The Book of Henry

    Sit on the black couch, sit on the bed, sit on the weird spinny office chair in HHQ. Sit seemed to be Nancys default. I sat down with a thump. She was the longest resident, so she taught me some stuff, just as shed taught Tess and Lorna when they first arrived. My head was whirling more than ever. Lyndsay said that, when shed arrived, another ghost had given her the Rules bookand told her to pass it on to whoever came in next before she left. So the Rules were passed down from dead girl to dead girl? But the rules clearly didnt help you solve your murder, I said.

    Youre still here. It might have, Nancy admitted quietly. Im sort of ninetynine percent sure who killed me. So why havent you gone through the Big Red Door? The words tumbled out before I had a chance to worry that it might be too early to ask something like that. Nancy looked down at her feet, tilting her head until a wave of her thick hair fell over her face. I guess I I dont want to move on yet, she said in a small voice.

    The information Lyndsay gave me when I first showed up here In helping me, um, come to terms with things. I kinda figured: if I could stick around and help other kids the way she helped me, then maybe I wouldnt have died in vain. What Im trying to say is that I have my reasons for sticking. Nancy gave me a small smile.

    You may find yours. Weve solved the murders of the lastwhat? She looked at Lorna for reassurance. Six kids who have come through these doors. Um, that did not sound like a Series-winning stat to me. It seems that when we die, some power in the Attesa takes our stories from out thereNancy pointed to the window where the outside world was going on as normalto here, and waved the ancient-looking letter she was still holding at me.

    One of these arrives just before each new ghost does. We dont know how or who sends it, but its always the same. It tells us basic information: your name, how, and when you died. So there was some spectral scribe out there sending letters about teenage deaths? Er, so if another one of those letter-things arrives, another dead kid is on the way? I managed. Well, yes, butaside from our current residentsits not often that we have two new ghosts here at the same time. I mean, it does happen. But if you look at the New York Times murder map, around seventy-four people are unlawfully killed each year in Manhattan and only six percent are under eighteen.

    Which means, in theory, we get less than one new case a month. Quite a manageable workload, wouldnt you say, Lorna? I tried not to audibly gulp. Now, as you can see from the board, both of your parents. We did some basic recon when we got your letter before your arrival, and the police had already ruled your death an accident.

    The Dead Girls Detective Agency by Suzy Cox

    Thats quick, really. Especially considering how you went. There must have been a real mess on the tracks, Lorna said. They shut down the F train line for a whole two hours for you. Two hours! And in rush hour. My final achievement. Man, I hoped Mom was getting that put on my gravestone. Here lies Charlotte Feldman. She pissed off commuters. Since the police have no clue you were murdered and in the absence of your murderer confessing in the next few days, finding out who pushed you is down to us, Nancy said.

    What murder squad wouldnt want a lineup like that? I better get some posters for my bedroom wall. I was going to be here for some time. Its the official dead girls Haunting Head Quarters. And the map? I just put it up on the wall because it helps me visualize a case. What about the sharks drawn in the Hudson? Did I really want to hear the answer? Was the river haunted by some Rule Four, Lorna said. Ghosts cant travel over water. Nancy just drew those in to show that we cant go in the river. I turned to Nancy hoping shed explain.

    Basically, ghosts are landlocked. Who knows why? Maybe so well stay in the city and concentrate on solving our cases. But if you are going to be stuck on an island, I cant imagine a better one than Manhattan, can you? Awesomeso now that I was dead and didnt appear to have a curfew, I still couldnt go and watch bands in Brooklyn. Double, triple, quadruple fun. Uh, unless I was about to find out that Rule 5 was that all teen ghosts did have a curfew after all.

    So is that it then? Are those all the Rules? No water walking, lots of crime solving, and dont forget to treat the hotel and everything in it like you would if you hadnt been pushed under a subway train? Nancy tucked her hair behind her ear. Oh no, there are a load more. She pointed to the thin red book. I just thought Id ease you in with the simple stuff. And what if I dont abide by these Rules?

    I was getting sick of all the dos and donts. What happens to me then? According to you, Im already dead. How much worse can it really get? Nancy looked shocked. Lorna actually looked up from her split ends. Had I gone too far? Now you sound like my kinda ghoul, a low voice deadpanned behind me.

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