Ms Elin H Davies: Rn

Ms Cecile M Ollivier: Bsc

Dr Agnes Saint

Cecile Ollivier
email: ollivierces@googlemail.com

Paediatric Investigation Plans for Pain: painfully slow!

Keywords: Paediatric, Pain, Clinical trials, Paediatric Regulation, Paediatric Committee (PDCO), Paediatric Investigation Plan (PIP) Paediatric, Pain, Clinical trials, Paediatric Regulation, Paediatric Committee (PDCO), Paediatric Investigation Plan (PIP)

Purpose: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA).

Methods: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis.

Results: From seventeen Paediatric Investigation Plans submitted, fourteen have resulted in EMA Decision, three were withdrawn by the applicants, eight were granted a full waiver from development, and one resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1282 children to be recruited into studies across five different products. Neonates were included in four of the products.

Conclusions:

The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.

The Paediatric Regulation [6] also brings in many new tasks and responsibilities for the European Medicines Agency (EMA), chief of which is the creation and operation of a Paediatric Committee (PDCO) within the Agency to provide objective scientific opinions on any development plan for medicines for use in children.

Since the Paediatric Regulation entered into force in January 2007, the regulatory environment for paediatric medicines has dramatically changed. The Regulation requires pharmaceutical companies to consider the needs of the paediatric population during the development of their medicinal product.

The objective of the Paediatric Regulation is to improve the health of children in Europe by:

• facilitating the development and availability of medicines for children aged 0 to 17 years,

• ensuring that medicines for use in children are of high quality, ethically researched, and authorised appropriately,

• improving the availability of information on the use of medicines for children, without:

• subjecting children to unnecessary trials,

• or delaying the authorisation of medicines for use in adults.

The paediatric regulation requires companies to submit a Paediatric Investigation Plan (PIPs; for further description of EMA terms see table 2) for their product, which is evaluated by the PDCO in 60 to 120 days.

There is a possible clock stop at D60 to allow companies to respond to requests for modification of the plan. PDCO opinions on PIPs and waivers are transformed into binding European Medicines Agency decisions [7].

The PIP is submitted for review by the PDCO no later than the completion of the relevant human pharmacokinetic studies in adults. A waiver can be granted for a specific product, an indication or a class of products based on of the following three grounds:

(i)
That the specific medicinal product or class of medicinal products is likely to be ineffective or unsafe in part or all of the paediatric population, (ii) That the disease or condition for which the specific medicinal product or class is intended occurs only in adult populations or (iii) That the specific medicinal product does not represent a significant therapeutic benefit over existing treatments.

For products already authorised, including active substances protected by a supplementary protection certificate, or by a patent eligible for a supplementary protection certificate, Article 8 of the Regulation applies. In these circumstances, companies have the obligation to submit the results of an agreed PIP covering all existing and For medicinal products not yet authorised Article 7 of the Regulation applies, and companies have the obligation to submit results of an agreed PIP, unless a waiver has been granted by the PDCO. Deferrals for the completion of trials (not for the submission of PIPs) can also be granted by the PDCO, to protect the safety of children until additional safety data in adults is available.

For off-patent products already available on the market for adults only, without information and/or a formulation appropriate for children of all ages Article 30 can apply, where companies submit a PIP on a voluntary basis leading to a Paediatric Use Marketing Authorisation (PUMA). The PIP must be agreed and covers paediatric indication and formulation. An overview of Article 7, 8 and 30 can be seen in Table 1.

Ethical concerns that too many vulnerable children are recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Within the context of a clinical trial safety monitoring can be done rigorously, and any safety concerns noted early on, minimised or prevented.

The PDCO is not responsible for marketing-authorisation applications for medicinal products for paediatric use.

This remains fully within the remit of the Committee for Medicinal Products for Human Use (CHMP) [1].

However, the CHMP or any other competent authority may request the PDCO to prepare an opinion on the quality, safety and efficacy of a medicinal product for use in the paediatric population if these data have been generated in accordance with an agreed paediatric investigation plan.

A review of all the PIPs submitted with a Decision reached between September 2007 and March 2010 was conducted to examine the impact of the Regulation in the therapeutic field of Pain, not only in terms of numbers of PIPs received but also in relation to the number and types of clinical trials to be conducted, and the number of children to be recruited. It also records scientific data, while streamlining work procedures by producing pre-filled documents and interacting directly with a secure e-mail system to send messages and documents to external addressees (including applicants).

Key word 'pain' was used in search fields 'condition/ indication' and therapeutic area as the main parameter to identify the PIPs of interest.

The Pain PIPs identified where then categorised according to type of product (

Results

Seventeen submissions were made to the Paediatric Committee (PDCO) for assessment. Three were withdrawn by the applicants during the procedure; the reasons for withdrawal were not communicated to the European Medicines Agency and PDCO.

Twelve submissions were for Article 7 and from a known class, with only one of the submissions being a product with a new mechanism of action. The thirteenth submission was for Article 8 and the fourteenth submission was a Paediatric Use Marketing Authorisation request, which was also a well known product widely used for other indications.

Seven out of the twelve Article 7 submissions were for fixed dose combinations, one of which included development in the adolescent age group while the other was an application for a full waiver. The PDCO did not consider that they offered significant therapeutic benefit to children as fixed combination. Although the effect of the substances on their own was known, the effect of the combination was unknown and would have required studies. However the PDCO was of the opinion that fixed combinations were not appropriate in this case as they do not allow flexibility in the dosing according to age and weight. Therefore waivers for paediatric development were granted for all age groups for these fixed combinations.

One eighth product was also a request for a Waiver in all age groups, based on the ground that the medicinal product did not represent a significant therapeutic benefit over existing available products. This submission was for an old product well known and widely used, but with a new formulation for intravenous use. In this instance, the PDCO did not agree that the product lacked the potential to meet the current needs; however they had significant concerns about the content of the formulation for this product and about the lack of clinical data for prescribing in the neonatal age group. Discussions with the company regarding these concerns led to the development of a clinical trial designed to specifically investigate these key safety concerns.

One of the Article 7 submission resulted in a negative opinion; the grounds for refusal cannot be communicated for legal reasons.

Finally out of the last three PIPs submissions under Article 7 were for the same active substance but included both acute and chronic pain indications, with immediate and prolonged release formulations. The initial application included a request for a partial waiver for the 0-23 months age group. Following extensive discussion with the applicant, the PDCO agreed on PIPs for all the paediatric age groups, in both indications but utilising modelling and simulation of pharmacokinetics in children less than 2 years.

The last PIP under Article 7 was for acute pain. The initial submission included a request for a partial waiver for the 0-23 months age group. Following discussion with the applicant, the PDCO agreed on PIPs for children from 6 years to less than 18 years and a partial waiver in children from birth to less than 6 years of age. The partial waiver was granted based on the ground that the product does not represent significant benefit over existing treatments.

The Article 8 PIP submission was refused by the PDCO. The PDCO had concerns that the proposed measures and timelines were not appropriate to generate necessary data in determining the conditions in which the medicinal product may be used to treat the paediatric population or subsets thereof, nor in adapting a paediatric formulation. The PDCO also considered that the product would not bring significant therapeutic benefit. A product-specific waiver was granted on PDCO own motion on the grounds that the specific medicinal product is likely to be ineffective or unsafe in all the paediatric population.

Another product submitted a request for a Waiver for children older than 2 years due to expected lack of efficacy in this age group and lack of significant therapeutic benefit. The PDCO was in agreement with the data presented by the applicant and therefore a Partial Waiver for children over 2 years of age was granted.

Overall, Opinions as issued by the PDCO following discussion with the applicant resulted in the agreement of 13 clinical trials, with a total of at least 1282 children to be recruited across five different products. The number of studies per product ranged from one to six.

For two of the products, the PDCO agreed to studies across the full paediatric age range (from birth to 18 years), starting with the older children (6 -17 years) and proceeding in a staggered stepwise manner to the younger children (2-5 years followed by the less than 2 years age group). This staggered approach was adopted to maximise the safety of the children.

Following extensive discussion between the PDCO and the company, efficacy did not need to be demonstrated in a blinded fashion in two clinical trials, on the grounds that data would be generated in other studies with the same compound, all be it in a different pain model.

Evaluation by the PDCO takes account where possible the guidance on Clinical Investigation of Medicinal Products for Treatment of Nociceptive Pain (Committee for Proprietary Medicinal Products (CPMP) [10] and the Guideline on Clinical Medicinal Products intended for the Treatment of Neuropathic Pain [11] Four studies for one product were placebo controlled, as there was no pharmacological alternative currently used or available in clinical practice. However, the study protocols included clear guidance for 'rescue treatment'.

Five other studies across three different products were active-controlled, however only two were blinded due to complexities in achieving this. Four of the studies were for pharmacokinetics only, and one of the studies was a modelling and simulation of pharmacokinetics.

Neonates were included in four agreed PIPs. Only one applicant had included neonates in their original PIP submission, and their inclusion in the other three PIPs was only after evaluation by PDCO, and subsequent discussions with the companies. Preterm neonates were included in two agreed PIPs, again following PDCO evaluation, with the primary aim of identify pharmacokinetics data in three PIPs. Population-pharmacokinetics, micro assay and sparse sampling were agreed in all four PIPs, limiting the individual burden for each infant. This is an important step forward given the lack of current available data for many drugs in the neonatal age group, while causing minimal pain and distress.

Three out of the five proposed PIPs were non-opioids intended for mild to moderate pain. One PIP was specifically for Procedural pain and the last PIP was for acute pain. Only the new product had the potential to work as Step III analgesia, as defined by the World Health Organization three-step analgesic ladder [2].

Formulations

The development of intravenous and age-appropriate oral formulation, in immediate and prolonged release forms, has the potential to be of significant therapeutic benefit to the paediatric population.

Eleven of the fourteen submissions included formulations for oral use, two of the fourteen included intravenous formulation, one submission was for inhalation use and the last submission was for nasal spray. Age-appropriate formulations were not adequately addressed in seven of the original submissions. Following review by the PDCO two of the applicants agreed to develop age-appropriate formulation. This would indicate that the legislation has been able to positively influence the development of age-appropriate formulations where it otherwise may not have been developed.

Discussion

Effective management of childhood pain is a high priority. There is now conclusive evidence that paediatric patients of all ages, including the extremely premature neonates [3], are capable of experiencing pain as a result of tissue injuries, medical illnesses, therapeutic and diagnostic procedures, trauma and surgery. A range of medications is available to treat a variety of pain types [4] but not all are suitable for all age subsets. There is increasing knowledge in the understanding of developmental neurobiology, developmental pharmacology and of the psychological needs of children in pain, however a gap remains.

The paediatric population (birth to 18 years) in the European Union is close to 100 million, and up to 10% of these will undergo some type of surgical procedures every year, not to mention other painful conditions.

Paediatric patients experience pain in different clinical situations following trauma, during hospital stay and in pathological conditions treated by physicians outside the hospital, such as headache and acute abdominal pain which are common during childhood. An epidemiological survey of 9,000 school children found that one third of seven year old children and half of 15 year olds had headaches. In a survey done in school children in Germany (n=749) [5] 83% of children and adolescents reported experiencing pain during the preceding 3 months. Many of these children, in all age groups will require analgesia.

Prior to the implementation of the Regulation the Paediatric Working Party a temporary working party of the Committee on Medicinal Products for Human Use (CHMP) -conducted an exercise between 2001 and 2007 to establish 'Paediatric Needs' [8]. The lists of paediatric needs as adopted by the Working Party serves as a basis for the inventory of needs that is to be established and published by the Paediatric Committee in accordance with the Paediatric Regulation. This list is intended to guide the Committee when assessing PIPs.

Another list, the 'Priority List of off-patent medicines' [9] has been set up to direct research on off-patent medicines for which there is a high need in the paediatric population. With the availability of funding, provided through the European Union Framework Programmes, the aim is that more of these medicines will be developed Pain management has one of the highest needs compared to other therapeutic areas, especially when considering the high incidence and prevalence of pain in the paediatric population across all conditions. When comparing the number of PIP submissions in pain to other therapeutic fields in the same time period however we note that the numbers of products being developed are small. In the same period, twenty-one PIPs were submitted in the therapeutic area of Diabetes (Twelve still under review), and twelve submitted for Human Immunodeficiency

Conclusion

There is an apparent lack of innovative drugs being developed for pain, compared to some other therapeutic areas, however this may not be a paediatric only problem. Despite the Paediatric Regulation industry remain at liberty to study in any therapeutic area of their choice. This is an opportune time for clinicians, academia, learned societies and industry to collaborate for the discovery of new products, the generation of new data and the development of new formulations to ultimately benefit the needs of children and neonates in pain. The Paediatric Regulation serves to enforce industry to consider the needs of children in the development plans of their products, while the PDCO serves to ensure that only studies that offer significant value are agreed upon for the final Decisions.

Commission of the European Communities:

The "civil service" of the European Union It is the executive organ of the Community. It proposes Community policy and legislation, implements the decisions taken by the Council of Ministers, and supervises the day-to-day running of Commission policies. Follow-up SA Any application for SA following the initial application on the same area/condition. For example, the initial advice can be on the pharmacokinetics and the exploratory phase II trial, and later the pivotal Phase III trial could be the subject of a follow-up advice.

Informed Consent applications

According to Article 10c of Directive 2001/83/EC as amended, following the granting of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, non clinical and clinical documentation contained in the dossier of the medicinal product for the purpose of examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form. http://www.ema.europa.eu/htms/human/presub/q03.htm MAA Marketing Authorisation Application: Across all European markets, plus Australia, New Zealand, South Africa, and Israel (exceptions amongst major markets include USA, Canada, China and Japan), the Marketing Authorization Application (MAA) is a common document used as the basis for a marketing application (an application for approval to market the product based on a full review of all quality, safety, and efficacy data, including clinical study reports).

In the USA, the New Drug Application (NDA) is the MAA equivalent. These are composed by experts of all Member States and are established in the legislation. In addition to the CHMP, the Committee for Advanced Therapies is also involved in the evaluation of medicinal products, in particular, gene, cell and tissue engineered medicinal products Single applications

In the European Union (EU), a company that wishes to bring a medicine to the market may submit a single application to the EMEA for a 'marketing authorisation' (licence) that is valid simultaneously in all EU Member States, plus Iceland, Liechtenstein and Norway. This is called the 'centralised (or 'Community') authorisation procedure', and is mandatory for certain types of medicines and optional for others. ( The objective of the Paediatric Regulation is to improve the health of children in Europe by:

• facilitating the development and availability of medicines for children aged 0 to 17 years,

• ensuring that medicines for use in children are of high quality, ethically researched, and authorised appropriately,

• improving the availability of information on the use of medicines for children, without:

• subjecting children to unnecessary trials,

• or delaying the authorisation of medicines for use in adults.

The paediatric regulation requires companies to submit a Paediatric Investigation Plan (PIPs; for further description of EMA terms see table 2) for their product, which is evaluated by the PDCO in 60 to 120 days.

There is a possible clock stop at D60 to allow companies to respond to requests for modification of the plan.

PDCO opinions on PIPs and waivers are transformed into binding European Medicines Agency decisions [7].

The PIP is submitted for review by the PDCO no later than the completion of the relevant human pharmacokinetic studies in adults. A waiver can be granted for a specific product, an indication or a class of products based on of the following three grounds: For medicinal products not yet authorised Article 7 of the Regulation applies, and companies have the obligation to submit results of an agreed PIP, unless a waiver has been granted by the PDCO. Deferrals for the completion of trials (not for the submission of PIPs) can also be granted by the PDCO, to protect the safety of children until additional safety data in adults is available.

For off-patent products already available on the market for adults only, without information and/or a formulation appropriate for children of all ages Article 30 can apply, where companies submit a PIP on a voluntary basis leading to a Paediatric Use Marketing Authorisation (PUMA). The PIP must be agreed and covers paediatric indication and formulation. An overview of Article 7, 8 and 30 can be seen in Table 1.

Ethical concerns that too many vulnerable children are recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Within the context of a clinical trial safety monitoring can be done rigorously, and any safety concerns noted early on, minimised or prevented.

The PDCO is not responsible for marketing-authorisation applications for medicinal products for paediatric use.

This remains fully within the remit of the Committee for Medicinal Products for Human Use (CHMP) [1].

However, the CHMP or any other competent authority may request the PDCO to prepare an opinion on the quality, safety and efficacy of a medicinal product for use in the paediatric population if these data have been generated in accordance with an agreed paediatric investigation plan.

A review of all the PIPs submitted with a Decision reached between September 2007 and March 2010 was conducted to examine the impact of the Regulation in the therapeutic field of Pain, not only in terms of numbers of PIPs received but also in relation to the number and types of clinical trials to be conducted, and the number of children to be recruited. It also records scientific data, while streamlining work procedures by producing pre-filled documents and interacting directly with a secure e-mail system to send messages and documents to external addressees (including applicants).

Key word 'pain' was used in search fields 'condition/ indication' and therapeutic area as the main parameter to identify the PIPs of interest.

The Pain PIPs identified where then categorised according to type of product (Table 2): Article 8 for products already authorised, Article 7 for medicinal products not yet authorised and for off-patent products already available on the market for adults only Article 30.

Key word 'diabetes', 'Human Immunodeficiency Virus (HIV)' and 'infectious diseases' were used in search fields 'condition/ indication' and therapeutic area as the main parameters to identify PIPs to be compared in term of numbers of pharmaceutical drugs that have been submitted with the therapeutic area of pain.

Results

Seventeen submissions were made to the Paediatric Committee (PDCO) for assessment. Three were withdrawn by the applicants during the procedure; the reasons for withdrawal were not communicated to the European Medicines Agency and PDCO.

Twelve submissions were for Article 7 and from a known class, with only one of the submissions being a product with a new mechanism of action. The thirteenth submission was for Article 8 and the fourteenth submission was a Paediatric Use Marketing Authorisation request, which was also a well known product widely used for other indications.

Seven out of the twelve Article 7 submissions were for fixed dose combinations, one of which included development in the adolescent age group while the other was an application for a full waiver. The PDCO did not consider that they offered significant therapeutic benefit to children as fixed combination. Although the effect of the substances on their own was known, the effect of the combination was unknown and would have required studies. However the PDCO was of the opinion that fixed combinations were not appropriate in this case as they do not allow flexibility in the dosing according to age and weight. Therefore waivers for paediatric development were granted for all age groups for these fixed combinations.

One eighth product was also a request for a Waiver in all age groups, based on the ground that the medicinal product did not represent a significant therapeutic benefit over existing available products. This submission was for an old product well known and widely used, but with a new formulation for intravenous use. In this instance, the PDCO did not agree that the product lacked the potential to meet the current needs; however they had significant concerns about the content of the formulation for this product and about the lack of clinical data for prescribing in the neonatal age group. Discussions with the company regarding these concerns led to the development of a clinical trial designed to specifically investigate these key safety concerns.

One of the Article 7 submission resulted in a negative opinion; the grounds for refusal cannot be communicated for legal reasons.

Finally out of the last three PIPs submissions under Article 7 were for the same active substance but included both acute and chronic pain indications, with immediate and prolonged release formulations. The initial application included a request for a partial waiver for the 0-23 months age group. Following extensive discussion with the applicant, the PDCO agreed on PIPs for all the paediatric age groups, in both indications but utilising modelling and simulation of pharmacokinetics in children less than 2 years.

The last PIP under Article 7 was for acute pain. The initial submission included a request for a partial waiver for the 0-23 months age group. Following discussion with the applicant, the PDCO agreed on PIPs for children from 6 years to less than 18 years and a partial waiver in children from birth to less than 6 years of age. The partial waiver was granted based on the ground that the product does not represent significant benefit over existing treatments.

The Article 8 PIP submission was refused by the PDCO. The PDCO had concerns that the proposed measures and timelines were not appropriate to generate necessary data in determining the conditions in which the medicinal product may be used to treat the paediatric population or subsets thereof, nor in adapting a paediatric formulation. The PDCO also considered that the product would not bring significant therapeutic benefit. A product-specific waiver was granted on PDCO own motion on the grounds that the specific medicinal product is likely to be ineffective or unsafe in all the paediatric population.

Another product submitted a request for a Waiver for children older than 2 years due to expected lack of efficacy in this age group and lack of significant therapeutic benefit. The PDCO was in agreement with the data presented by the applicant and therefore a Partial Waiver for children over 2 years of age was granted.

Overall, Opinions as issued by the PDCO following discussion with the applicant resulted in the agreement of 13 clinical trials, with a total of at least 1282 children to be recruited across five different products. The number of studies per product ranged from one to six.

For two of the products, the PDCO agreed to studies across the full paediatric age range (from birth to 18 years), starting with the older children (6 -17 years) and proceeding in a staggered stepwise manner to the younger children (2-5 years followed by the less than 2 years age group). This staggered approach was adopted to maximise the safety of the children.

Following extensive discussion between the PDCO and the company, efficacy did not need to be demonstrated in a blinded fashion in two clinical trials, on the grounds that data would be generated in other studies with the same compound, all be it in a different pain model.

Evaluation by the PDCO takes account where possible the guidance on Clinical Investigation of Medicinal Products for Treatment of Nociceptive Pain (Committee for Proprietary Medicinal Products (CPMP) [10] and the Guideline on Clinical Medicinal Products intended for the Treatment of Neuropathic Pain [11] Four studies for one product were placebo controlled, as there was no pharmacological alternative currently used or available in clinical practice. However, the study protocols included clear guidance for 'rescue treatment'.

Five other studies across three different products were active-controlled, however only two were blinded due to complexities in achieving this. Four of the studies were for pharmacokinetics only, and one of the studies was a modelling and simulation of pharmacokinetics.

Neonates were included in four agreed PIPs. Only one applicant had included neonates in their original PIP submission, and their inclusion in the other three PIPs was only after evaluation by PDCO, and subsequent discussions with the companies. Preterm neonates were included in two agreed PIPs, again following PDCO evaluation, with the primary aim of identify pharmacokinetics data in three PIPs. Population-pharmacokinetics, micro assay and sparse sampling were agreed in all four PIPs, limiting the individual burden for each infant. This is an important step forward given the lack of current available data for many drugs in the neonatal age group, while causing minimal pain and distress.

Three out of the five proposed PIPs were non-opioids intended for mild to moderate pain. One PIP was specifically for Procedural pain and the last PIP was for acute pain. Only the new product had the potential to work as Step III analgesia, as defined by the World Health Organization three-step analgesic ladder [2].

Formulations

The development of intravenous and age-appropriate oral formulation, in immediate and prolonged release forms, has the potential to be of significant therapeutic benefit to the paediatric population.

Eleven of the fourteen submissions included formulations for oral use, two of the fourteen included intravenous formulation, one submission was for inhalation use and the last submission was for nasal spray. Age-appropriate formulations were not adequately addressed in seven of the original submissions. Following review by the PDCO two of the applicants agreed to develop age-appropriate formulation. This would indicate that the legislation has been able to positively influence the development of age-appropriate formulations where it otherwise may not have been developed.

Discussion

Effective management of childhood pain is a high priority. There is now conclusive evidence that paediatric patients of all ages, including the extremely premature neonates [3], are capable of experiencing pain as a result of tissue injuries, medical illnesses, therapeutic and diagnostic procedures, trauma and surgery. A range of medications is available to treat a variety of pain types [4] but not all are suitable for all age subsets. There is increasing knowledge in the understanding of developmental neurobiology, developmental pharmacology and of the psychological needs of children in pain, however a gap remains.

The paediatric population (birth to 18 years) in the European Union is close to 100 million, and up to 10% of these will undergo some type of surgical procedures every year, not to mention other painful conditions.

Paediatric patients experience pain in different clinical situations following trauma, during hospital stay and in pathological conditions treated by physicians outside the hospital, such as headache and acute abdominal pain which are common during childhood. An epidemiological survey of 9,000 school children found that one third of seven year old children and half of 15 year olds had headaches. In a survey done in school children in Germany (n=749) [5] 83% of children and adolescents reported experiencing pain during the preceding 3 months. Many of these children, in all age groups will require analgesia.

Prior to the implementation of the Regulation the Paediatric Working Party a temporary working party of the Committee on Medicinal Products for Human Use (CHMP) -conducted an exercise between 2001 and 2007 to establish 'Paediatric Needs' [8]. The lists of paediatric needs as adopted by the Working Party serves as a basis for the inventory of needs that is to be established and published by the Paediatric Committee in accordance with the Paediatric Regulation. This list is intended to guide the Committee when assessing PIPs.

Another list, the 'Priority List of off-patent medicines' [9] has been set up to direct research on off-patent medicines for which there is a high need in the paediatric population. With the availability of funding, provided through the European Union Framework Programmes, the aim is that more of these medicines will be developed Pain management has one of the highest needs compared to other therapeutic areas, especially when considering the high incidence and prevalence of pain in the paediatric population across all conditions. When comparing the number of PIP submissions in pain to other therapeutic fields in the same time period however we note that the numbers of products being developed are small. In the same period, twenty-one PIPs were submitted in the therapeutic area of Diabetes (Twelve still under review), and twelve submitted for Human Immunodeficiency

Conclusion

There is an apparent lack of innovative drugs being developed for pain, compared to some other therapeutic areas, however this may not be a paediatric only problem. Despite the Paediatric Regulation industry remain at liberty to study in any therapeutic area of their choice. This is an opportune time for clinicians, academia, learned societies and industry to collaborate for the discovery of new products, the generation of new data and the development of new formulations to ultimately benefit the needs of children and neonates in pain. The Paediatric Regulation serves to enforce industry to consider the needs of children in the development plans of their products, while the PDCO serves to ensure that only studies that offer significant value are agreed upon for the final Decisions.

IntroductionA

  new piece of legislation (Regulation (EC) No 1901/2006 as amended) namely the 'Paediatric Regulation' governing the development and authorisation of medicines for use in children aged 0 to 17 years was introduced in the European Union in January 2007.

  new route of administration or new formulation, unless a waiver has been granted by the PDCO.

FormattedMethod

  Utilising the EMA Paediatric Database, all the Paediatric Investigation Plans (PIPs) received by the EMA between September 2007 and March 2010 were searched to identify those in the therapeutic field of pain.The EMA Paediatric Database includes all PIPs and/or waivers submitted to the PDCO and EMA since June 2007 along with all procedural steps leading to the PDCO Opinion and European Medicines Agency decision (outcome).

Formatted

Formatted

Formatted

  for children and submitted for a Paediatric Use Marketing Authorisation. Conditions with higher therapeutic needs were initially identified as early as 2002-2003, mostly based on the severity of the disease; the paediatric groups affected (with special priority for the neonatal population); the non-availability of treatment alternatives; and the high prevalence of the disease in the paediatric population. For each condition, published therapeutic reviews of medicines used in children were analysed to identify off-label products of therapeutic interest and priorities for research. The list comprises a number of medicines relating to various therapeutic areas and is regularly updated. Analgesia in the paediatric population was identified as an area with high therapeutic needs in the 'Priority List' and in the 'Paediatric Needs'.

FormattedFormatted

  Nine still under review). The prevalence and incidence of these indications compared to pain (five still under review) are comparatively much less, but are noted to be very active areas in terms of drug development.Development in Pain is low in comparison to the high incidence and despite the high therapeutic need identified in the priority list.

  of legislation (Regulation (EC) No 1901/2006 as amended) namely the 'Paediatric Regulation' governing the development and authorisation of medicines for use in children aged 0 to 17 years was introduced in the European Union in January 2007. The Paediatric Regulation [6] also brings in many new tasks and responsibilities for the European Medicines Agency (EMA), chief of which is the creation and operation of a Paediatric Committee (PDCO) within the Agency to provide objective scientific opinions on any development plan for medicines for use in children. Since the Paediatric Regulation entered into force in January 2007, the regulatory environment for paediatric medicines has dramatically changed. The Regulation requires pharmaceutical companies to consider the needs of the paediatric population during the development of their medicinal product.

  (i)That the specific medicinal product or class of medicinal products is likely to be ineffective or unsafe in part or all of the paediatric population, (ii) That the disease or condition for which the specific medicinal product or class is intended occurs only in adult populations or (iii) That the specific medicinal product does not represent a significant therapeutic benefit over existing treatments.For products already authorised, including active substances protected by a supplementary protection certificate, or by a patent eligible for a supplementary protection certificate, Article 8 of the Regulation applies. In these circumstances, companies have the obligation to submit the results of an agreed PIP covering all existing and new route of administration or new formulation, unless a waiver has been granted by the PDCO.

Method

  Utilising the EMA Paediatric Database, all the Paediatric Investigation Plans (PIPs) received by the EMA between September 2007 and March 2010 were searched to identify those in the therapeutic field of pain.The EMA Paediatric Database includes all PIPs and/or waivers submitted to the PDCO and EMA since June 2007 along with all procedural steps leading to the PDCO Opinion and European Medicines Agency decision (outcome).

  for children and submitted for a Paediatric Use Marketing Authorisation. Conditions with higher therapeutic needs were initially identified as early as 2002-2003, mostly based on the severity of the disease; the paediatric groups affected (with special priority for the neonatal population); the non-availability of treatment alternatives; and the high prevalence of the disease in the paediatric population. For each condition, published therapeutic reviews of medicines used in children were analysed to identify off-label products of therapeutic interest and priorities for research. The list comprises a number of medicines relating to various therapeutic areas and is regularly updated. Analgesia in the paediatric population was identified as an area with high therapeutic needs in the 'Priority List' and in the 'Paediatric Needs'.

Table 2 )

 2 : Article 8 for products already authorised, Article 7 for medicinal products not yet authorised and for off-patent products already available on the market for adults only Article 30.Key word 'diabetes', 'Human Immunodeficiency Virus (HIV)' and 'infectious diseases' were used in search fields 'condition/ indication' and therapeutic area as the main parameters to identify PIPs to be compared in term of numbers of pharmaceutical drugs that have been submitted with the therapeutic area of pain.

	Formatted: Not Highlight

Table 1

 1 A short description of EMA terms including weblinks (updated from Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency (Eur J Clin Pharmacol (2010) 66:39-48). Community registration procedure created by Council Regulation (EEC) No. 2309/93 and amended by Regulation 726/2004 for the authorization of medicinal products, for which there is a single application, a single evaluation and a single authorisation allowing direct access to the single market of the European Community. The opinion of the CHMP is transmitted to the European Commission to be transformed in a further 67 days into a single marketing authorisation applicable to the whole European Union. This procedure is compulsory for medicinal products derived from biotechnology, and in 4 specific therapeutic areas (products against HIV, cancer, neurodegenerative diseases and diabetes), and available at the request of companies for other innovative new products. Applications are submitted directly to the EMEA. http://ec.europa.eu/enterprise/pharmaceuticals/procedure/cproc_en.htm http://www.ema.europa.eu/index/authorisation.htm Class waiver The Agency already adopted decisions on class waivers in October 2009 for conditions that do not occur in children, or for products likely to be unsafe or ineffective in children. The list of waivers is regularly updated in light of the advance in knowledge and science in the paediatric field. http://www.ema.europa.eu/htms/human/paediatrics/classwaivers.htm CHMP The Committee for Medicinal Products for Human Use (CHMP) is responsible for preparing the Agency's opinions on all questions concerning medicinal products for human use, in accordance with Regulation (EC) No 726/2004. http://www.ema.europa.eu/htms/general/contacts/CHMP/CHMP.html CHMP Opinion CHMP's scientific conclusions on issues related to medicinal products, e.g. whether the data submitted allow to conclude that there is an overall positive benefit/risk of a new product in a proposed indication and whether the product should be placed on the market. Compliance A compliance check is performed to verify that all the measures agreed in a PIP and reflected in the Agency's decision have been conducted in accordance with the decision, including the agreed timelines. Compliance is one of several prerequisites for obtaining the rewards and incentives provided for in Articles 36 to 38 of the Paediatric Regulation. EMA The European Medicines Agency (EMA) created by Council Regulation (EEC) No. 2309/93 of 22 July 1993, and renamed by Council Regulation 726/2004 of 31 March 2004, is based in Canary Wharf, London. The Agency is responsible for coordinating the existing scientific resources put at its disposal by the competent authorities of the Member States for the evaluation and supervision of medicinal products.

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http://www.ema.europa.eu European Commission

  Medicinal ProductA finished dosage form, for example, tablet, capsule, solution, etc., that contains an active ingredient generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo.Multiple ApplicationsMAAs, where the applicants wish to obtain, either simultaneously or successively, more than one Marketing Authorisation for a specific medicinal product, under different invented names. http://www.ema.europa.eu/htms/human/presub/q09.htm OD Orphan Drug A drug for the treatment of a rare serious disease (defined in the EU as a condition that affects not more than 5 in 10,000 persons in the Community, and in the US as a condition affecting fewer than 200,000 people in the US) or for a disease not likely to generate sufficient profit to justify R&D costs. http://www.ema.europa.eu/htms/human/orphans/intro.htm PDCOThe main responsibility of the Paediatric Committee (PDCO) is to assess the content of paediatric investigation plans and adopt opinions on them in accordance with Regulation (EC) 1901/2006 as amended. This includes the assessment of applications for a full or partial waiver and assessment of applications for deferrals http://www.ema.europa.eu/htms/general/contacts/PDCO/PDCO.html PIP A PIP sets out a programme for the development of a medicine in the paediatric population.The PIP aims to generate the necessary quality, safety and efficacy data through studies to support the authorisation of the medicine for use in children of all ages including ageappropriate formulation(s). These data have to be submitted to the European Medicines Agency, or national competent authorities, as part of an application for a marketing authorisation for a new medicine, or for one covered by a patent. In some cases, a PIP may include a waiver of the studies in one or more paediatric subsets, or a deferral.

	Protocol Assistance SA SA letter	The process of giving scientific advice for Orphan Drugs F http://www.ema.europa.eu/htms/human/sciadvice/protocol.htm Scientific Advice http://www.emea.europa.eu/htms/human/sciadvice/Scientific.htm o An official written statement expressing the final opinion of the CHMP on the questions raised r by the applicant.
		P
		e
		e r
		R
		e
		v i e
		w
		In Canada, the New
		Drug Submission (NDS) is the MAA equivalent.
		http://www.ema.europa.eu/index/indexh1.htm

SAWP

The Scientific Advice Working Party is a permanent working party of the CHMP, in charge of Scientific Advice and Protocol Assistance for orphan medicinal products. This is the only Working Party of the EMEA established in the EU legislation http://www.ema.europa.eu/htms/general/contacts/CHMP/CHMP_SAWP.html. Scientific Committees

Table 2 :

 2 Partyare composed of members selected from the European experts list maintained by the EMEA. http://www.ema.europa.eu/htms/general/contacts/CHMP/CHMP_WPs.html An overview of Article 7, 8 and 30

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		The precise scope is set out in Annex I of
		Regulation (EC) No 726/2004.)
		http://www.ema.europa.eu/index/indexh1.htm
	SMEs	Small and Medium-sized Enterprises
		Companies are classified according to their size (micro, small or medium) based on the number
		of employees and annual turnover.
		http://www.ema.europa.eu/htms/human/raguidelines/sme.htm
	Variation	Modification to the terms of a marketing authorization application (Regulations (EEC) No
		2309/93 and Directives 2001/83/EC and 2001/82/EC),. Variations can be minor (type IA and
		IB) or major (type II), (Commission Regulation (EC) No 1084/2003)
		http://www.ema.europa.eu/htms/human/raguidelines/post.htm -type1
		http://www.ema.europa.eu/htms/human/raguidelines/post.htm -type2
	Waiver	Waivers can be issued if there is evidence that the medicine concerned is likely to be ineffective
		or unsafe in the paediatric population, or that the disease or condition targeted occurs only in
		adult populations, or that the medicine, or the performance of trials, does not represent a
		significant therapeutic benefit over existing treatments for paediatric patients.
	Withdrawal	An applicant withdraws the application for evaluation of a medicinal product
		http://www.ema.europa.eu/htms/human/withdraw/withdrawapp/background.htm
	Working	The CHMP establishes working parties which have expertise in a particular scientific field, and

  Partyare composed of members selected from the European experts list maintained by the EMEA. http://www.ema.europa.eu/htms/general/contacts/CHMP/CHMP_WPs.html

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	16

European Journal of Clinical Pharmacology

Acknowledgements

The authors would like to thank the Paediatric Committee and the paediatric team at the European Medicines Agency who contribute every day to make better medicines for children. We are very grateful for the cooperation of the children and parents who take part in the clinical research and hope that children will soon benefit from the Paediatric Regulation. It would not be possible without their help and cooperation.

Acknowledgements

The authors would like to thank the Paediatric Committee and the paediatric team at the European Medicines Agency who contribute every day to make better medicines for children. We are very grateful for the cooperation of the children and parents who take part in the clinical research and hope that children will soon benefit from the Paediatric Regulation. It would not be possible without their help and cooperation.

Conflict of interest

The authors declare that they have no conflict of interest. Virus. (Nine still under review). The prevalence and incidence of these indications compared to pain (five still under review) are comparatively much less, but are noted to be very active areas in terms of drug development.

Development in Pain is low in comparison to the high incidence and despite the high therapeutic need identified in the priority list.

Conflict of interest

The authors declare that they have no conflict of interest.

Commission of the European Communities:

The "civil service" of the European Union It is the executive organ of the Community. It proposes Community policy and legislation, implements the decisions taken by the Council of Ministers, and supervises the day-to-day running of Commission policies. Follow-up SA Any application for SA following the initial application on the same area/condition. For example, the initial advice can be on the pharmacokinetics and the exploratory phase II trial, and later the pivotal Phase III trial could be the subject of a follow-up advice.

Informed Consent applications

According to Article 10c of Directive 2001/83/EC as amended, following the granting of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, non clinical and clinical documentation contained in the dossier of the medicinal product for the purpose of examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form. These are composed by experts of all Member States and are established in the legislation. In addition to the CHMP, the Committee for Advanced Therapies is also involved in the evaluation of medicinal products, in particular, gene, cell and tissue engineered medicinal products Single applications

In the European Union (EU), a company that wishes to bring a medicine to the market may submit a single application to the EMEA for a 'marketing authorisation' (licence) that is valid simultaneously in all EU Member States, plus Iceland, Liechtenstein and Norway. This is called the 'centralised (or 'Community') authorisation procedure', and is mandatory for certain types of medicines and optional for others. (


MD David Gyllenberg
email: david.gyllenberg@helsinki.fi

MD, PhD Andre Sourander

MD, PhD Solja Niemelä

MSc Hans Helenius

BA Lauri Sillanmäki

MD, PhD Jorma Piha

MD, PhD Kirsti Kumpulainen

MD, PhD Tuula Tamminen

MD, PhD Irma Moilanen

MD, PhD Fredrik Almqvist

Childhood predictors of later psychiatric hospital treatment: findings from the Finnish 1981 birth cohort study

Keywords: Epidemiology, Child Psychiatry, Health services, Comorbidity, Cohort studies

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Psychiatric hospital treatment (PHT) is the most expensive mental health care treatment [START_REF] Mechanic | Changing patterns of psychiatric inpatient care in the united states, 1988-1994[END_REF] and indicates a severe psychiatric disorder [START_REF] Blanz | Preconditions and outcome of inpatient treatment in child and adolescent psychiatry[END_REF]. PHT becomes more common in adolescence [START_REF] Pottick | Factors associated with inpatient and outpatient treatment for children and adolescents with serious mental illness[END_REF] and is associated with psychotic, affective [START_REF] Pottick | Factors associated with inpatient and outpatient treatment for children and adolescents with serious mental illness[END_REF] and comorbid disorders, high rates of aggressive behavior [START_REF] Gowers | Inpatient services[END_REF], suicidality [START_REF] Olfson | National trends in hospitalization of youth with intentional self-inflicted injuries[END_REF] and an elevated risk of death before middle age [START_REF] Best | Adolescent psychiatric hospitalization and mortality, distress levels, and educational attainment: Follow-up after 11 and 20 years[END_REF]. In order to prevent these severe disorders and reduce the high health costs, it is important to early identify those at highest risk. Clinical case-control longitudinal studies have shown that children with a psychiatric diagnosis are at risk of PHT in adulthood [START_REF] Knapp | The Maudsley long-term follow-up of child and adolescent depression: 3. Impact of comorbid conduct disorder on service use and costs in adulthood[END_REF][START_REF] Weissman | Children with prepubertal-onset major depressive disorder and anxiety grown up[END_REF]. However, the only large-scale prospective birth cohort study examining childhood predictors for later PHT with a follow-up extending to adulthood is the UK National Child Development Study (UKNCDS) [START_REF] Done | Childhood antecedents of schizophrenia and affective illness: Social adjustment at ages 7 and 11[END_REF]. The study included 131 inpatients and 1385 randomly selected controls. Among males, teacher reports of externalizing and internalizing behaviors both at age seven and age eleven predicted hospital treatment of psychosis or neurotic disorders before the age of 28. Conversely among females, problems at age seven did not substantially increase the likelihood of PHT, whereas problems at age eleven increased the likelihood.

Previous studies regarding childhood predictors for later PHT are scarce and several issues have been overlooked. First, the scarcity of gender-specific studies in this field is understandable, since PHT is a rather rare phenomenon, and the number of subjects has not exceeded 1000 participants in most psychiatric birth cohort studies including information both about childhood psychopathology and adult psychiatric outcomes.

Second, childhood comorbid conduct and emotional problems increase the risk of several adult adverse outcomes [START_REF] Ensminger | Childhood and adolescent antecedents of substance use in adulthood[END_REF][START_REF] Foley | Proximal psychiatric risk factors for suicidality in youth: The great smoky mountains study[END_REF][START_REF] Knapp | The Maudsley long-term follow-up of child and adolescent depression: 3. Impact of comorbid conduct disorder on service use and costs in adulthood[END_REF][START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF][START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF], but its impact on later PHT remains unclear. Third, in the UKNCDS, childhood mental health problems relied only on teacher reports at baseline [START_REF] Done | Childhood antecedents of schizophrenia and affective illness: Social adjustment at ages 7 and 11[END_REF]. However, information about childhood problems should be based on standardized tools from several informants to get a comprehensive view of the child's problems [START_REF] Costello | 10-year research update review: The epidemiology of child and adolescent psychiatric disorders: I. methods and public health burden[END_REF].

The current study aims to fill the previously described gaps in the literature by examining in an explorative manner the predictive associations between childhood psychiatric problems at age eight (externalizing, internalizing, combinations of them, parent/teacher versus child self-reports) and the timing of PHT and separate diagnostic groups between age 13 and 24. We used a nationwide birth cohort, consisting of one tenth of all eight-year-olds born in Finland in 1981, and linked it 16 years later to the Finnish National Hospital Discharge Register [START_REF] Gissler | Finnish health and social welfare registers in epidemiological research[END_REF]28,[START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF][START_REF] Tiihonen | Premorbid intellectual functioning in bipolar disorder and schizophrenia: Results from a cohort study of male conscripts[END_REF]. Because of the sex differences in disorder prevalence through childhood and adolescence [START_REF] Rutter | Using sex differences in psychopathology to study causal mechanisms: Unifying issues and research strategies[END_REF][START_REF] Simonoff | The Virginia twin study of adolescent behavioral development. Influences of age, sex, and impairment on rates of disorder[END_REF] and the differing developmental pathways in the sexes [START_REF] Hankin | Development of gender differences in depression: An elaborated cognitive vulnerability-transactional stress theory[END_REF][START_REF] Rutter | Using sex differences in psychopathology to study causal mechanisms: Unifying issues and research strategies[END_REF], we performed all analyses separately for males and females.

MATERIAL AND METHODS

Participants

This investigation is part of the nationwide "Finnish 1981 Birth Cohort Study". The Joint Commission on Ethics of Turku University and Turku University Central Hospital has approved the research plan. Informed consent was obtained from the children's parents at baseline. The combination of information from questionnaires and registry data was analyzed in such a way that the subject could not be identified.

The methodology of the study has been reported in detail previously [START_REF] Almqvist | Design and subjects of a Finnish epidemiological study on psychiatric disorders in childhood[END_REF][START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF][START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF]. The original representative study sample was drawn from the Finnish-speaking population of Finnish children born during 1981 (n=60,007). The first assessment was conducted in October and November 1989. Of the selected 8-9-year-old 6017 children, 5813 (96.6%) took part in the study in 1989. The sample was controlled for demographic and socio-economic factors in the general population and it has good generalizability [START_REF] Almqvist | Design and subjects of a Finnish epidemiological study on psychiatric disorders in childhood[END_REF]. At follow-up, we identified the subjects in our cohort by linking their unique identification number with the Hospital Register Data. Subjects were excluded if their unique personal identification codes were lost or could not be linked with the Hospital Discharge Register, or if they had died or moved between 1989 and 1993. Of the 5813 children studied in 1989, information about inpatient hospital service use between 1994 and 2005 was obtained for 5346 subjects (91.9%; 2710 males (M) and 2636 females (F)).

Methods

Mental health problems at age eight Psychiatric symptoms at age eight were assessed using information collected from three different sources: parents, teachers, and children. The parents and the teachers completed the Rutter's parent questionnaire [START_REF]Education, health and behaviour[END_REF] and the teacher-questionnaire [START_REF] Rutter | A children's behaviour questionnaire for completion by teachers: Preliminary findings[END_REF], respectively. Both scales are validated [START_REF] Kresanov | Validity of child psychiatric screening methods[END_REF] and have been widely used in child psychiatric research [START_REF] Almqvist | Design and subjects of a Finnish epidemiological study on psychiatric disorders in childhood[END_REF]. The parent questionnaire consists of 31 and the teacher questionnaire of 26 items on a scale ranging between 0 and 2 points, giving a maximum total score of 62 and 52 points respectively. In addition to the total score scale, there are three subscales. The conduct scale has questions about stealing, lying, aggression, defiance; the attention-hyperactivity scale has concerns about restlessness, distractibility, inattention; and the emotional scale addresses shyness, withdrawal and anxiety. The children themselves filled in the Children's Depression Inventory (CDI), which measures depressive symptoms [START_REF] Kovacs | Children's Depression Inventory[END_REF]. The CDI has shown good validity for assessing depressive symptoms among children [START_REF] Timbremont | Assessing depression in youth: Relation between the children's depression inventory and a structured interview[END_REF]. It has 27 items on a scale ranging between 0 and 2 points, but the question concerning suicide was excluded from our version, because it was thought that it could upset the children [START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF]. In sum, our version had a maximum score of 52 points. The agreement between informants and the sex specific scores of the subscales have been reported previously [START_REF] Almqvist | Behavioural and emotional symptoms in 8-9-year-old children[END_REF].

First, to assess possible caseness, the children were divided into screen positive and negative groups. The total scores of the parent and teacher reports (M: n=2638; F: n=2554) were cut off at 13 and 9 points, respectively, which correspond to the 85th percentile: these are commonly used, and validated to detect mental disorders [START_REF] Kresanov | Validity of child psychiatric screening methods[END_REF].

Parent and teacher reports were combined using an "or rule" [START_REF] Jensen | Parent and child contributions to diagnosis of mental disorder: Are both informants always necessary?[END_REF][START_REF] Youngstrom | Who are the comorbid adolescents? Agreement between psychiatric diagnosis, youth, parent, and teacher report[END_REF], i.e. subjects were classed as screen positive if either the parent report or the teacher report or both reports were above the cutoff score (M: 29.6%; F: 12.6%). The proportions of screen positive and screen negative subjects have been described in detail in a prior report [START_REF] Almqvist | Behavioural and emotional symptoms in 8-9-year-old children[END_REF].

Second, to study specific types of psychopathology, four scales were used: the pooled conduct, attentionhyperactivity and emotional scales and the self-reported depressive scale [START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF][START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF]. The scores from the parent and teacher conduct, attention-hyperactivity and emotional subscales were summed together to generate the three pooled scales (parent conduct scores + teacher conduct scores = pooled conduct score etc.), while the depressive scale was based on the child self-report alone. These scales were studied as both linear variables to achieve statistical power and as categorical variables to facilitate the interpretation of the results for screening purposes. In line with previous reports using categorical variables [START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF][START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF], we used sex-specific cutoff scores at the 90th percentile based on the distribution in the population-based sample at baseline. Third, to analyze how combinations of psychopathology affect the outcome, the pooled categorical conduct, attention-hyperactivity, emotional and depressive scales were combined (M: n=2544; F: n=2471). Sixteen different combinations of symptoms were formed by the four categorical scales. The 16 groups were collapsed into six clinically meaningful groups in line with previous reports [START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF][START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF]: 1. The Reference group was negative (below the 90th percentile) on all four scales (M: 69.9%; F: 70.6%); 2. The Conduct-emotional group was conduct-positive and emotional-positive or CDI-positive, indicating a high level of symptoms in both conduct and emotional domains (M: 4.3%; F: 3.5%); 3. The Conduct-only group was positive on the conduct scale, but negative on both the emotional scale and the CDI (M: 5.7%; F: 7.8%); 4. The Attention-Hyperactivity group was positive on the attention-hyperactivity scale, but without conduct problems (M: 4.0%; F: 5.6%); 5. The Emotional-only group was positive on the emotional scale or the CDI, but negative on conduct and attentionhyperactivity scales (M: 9.6%; F: 6.7%); 6. The Invisible group had high levels of self-reported depressive symptoms, but was screen negative on all three scales based on adult reports (M: 6.5%; F: 5.7%).

Additional data at age eight was collected on: (1) parental education level: father's or mother's completion of at least 12 years of education (in Finland compulsory education consists of 9-year comprehensive school after which education can be continued in vocational school or in upper secondary school concentrating on theoretical subjects); (2) family structure: families were classified as intact (two-biological-parent families) or non-intact (other family structure).

The outcome

Information about psychiatric hospital treatment between 1.1.1994 and 31.12.2005 was based on the National Hospital Register in Finland, which is extensively documented in psychiatric research [START_REF] Keskimäki | Accuracy of data on diagnoses, procedures and accidents in the Finnish hospital discharge register[END_REF]28,[START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF][START_REF] Tiihonen | Premorbid intellectual functioning in bipolar disorder and schizophrenia: Results from a cohort study of male conscripts[END_REF]. The register covers the diagnosis and the day of admission in all general, mental and private hospital inpatient care units in Finland. If a patient needs observation for more than 12 hours, the patient is admitted to a inpatient treatment [START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF].

The outcome of psychiatric hospital treatment was defined as having a primary diagnosis of a psychiatric disorder in the hospital discharge register between 1994 and 2005. All patients treated according to the register were included in the study. The diagnostic codes were registered according to ICD-9 in years 1994-1995 and ICD-10 in 1996-2005. Diagnostic codes of specific diagnoses and diagnostic groups were classified according to the transcription of ICD-10 and ICD-9 codes to DSM-IV-TR diagnoses [START_REF]Appendix H. DSM-IV classification with ICD-10 codes[END_REF]. The association with childhood variables was analyzed for having any psychiatric diagnosis and additionally separately analyzed for the four diagnostic groups with most subjects: psychosis, mood disorders (non-psychotic), anxiety disorders, and substance-related disorders. Subjects could belong to several diagnostic groups, because some subjects were diagnosed with different diagnoses at different admissions. Subjects who had not been treated for a psychiatric disorder according to the register data between 1994 and 2005 were used as a reference group in all statistical analyses.

Statistical Analysis

Associations of psychiatric symptoms with incidence of PHT and the four diagnostic groups between ages 13 and 24 years were analyzed using Cox's proportional hazards regression analysis [START_REF] Hoshmer | Applied Survival Analysis, Regression Modeling of Time to Event Data[END_REF]. The time from age 13 to the first hospital admission with a certain type of diagnosis before age 24 was the observed time for an endpoint event in the analyses. For those who did not have any hospital treatment before age 24, the time from age 13 to age 24 was recorded as the event time, and it was handled as a censored time observation. The strength of the associations was quantified using hazard ratios (HR) with 95% confidence intervals (95%CI). The Kaplan-Meier curves in the figures were Nelson (empirical) cumulative hazard function estimates. Statistical computations were done with SAS System for Windows, release 9.1/2006.

RESULTS

Psychiatric Hospital Treatment between Age 13 and 24

During the follow-up, 168 (6.2%) males and 108 (4.1%) females had been admitted for psychiatric treatment.

The mean age at their first admission was 19.1 (SD 2.4) for males and 18.8 (SD 3.7) for females. A detailed table of the number of subjects who had been admitted for different specific psychiatric diagnoses, is available from the corresponding author upon request. The most common psychiatric reason (diagnostic group) for being admitted to hospital treatment among males was substance-related disorders (1.8%, n=48), while among females it was non-psychotic mood disorders (1.9%, n=50). Males (1.5%, n=40) were more often than females (.8%, n=22) admitted for psychotic disorders (Fisher's exact test, subjects without the studied diagnosis were used as reference group, p=.030). More males than females were admitted for non-affective psychoses (1.3%, n=35 vs.

.5%, n=13, p=.002), and two of its six sub-diagnoses: schizophrenia (.6%, n=15 vs. .2%, n=4, p=.019) and psychotic disorder not otherwise specified (.8%, n=22 vs. .2%, n=5, p=.002). No sex differences were seen among affective psychoses (.4%, n=10 vs. .4%, n=11, p=.83). Some subjects had several admissions with different primary diagnoses. The rate of overlapping of different diagnostic groups during the follow-up is available from the corresponding author upon request. Among males, diagnostic groups overlapped with each other between 4.2% and 30.0%, while among females, the groups overlapped between 8.0% and 40.9%.

Predictors at Age eight for Psychiatric Hospital Treatment

Screen positive at age eight: As shown in Figures a andb, the probability of surviving without PHT decreased more for the screen-positive group than for the screen-negative group throughout the follow-up period in both sexes. However, among males, there was an increase in subjects being admitted for the first time for PHT during the follow-up between the age of 18 and 22 in both the screen-positive and screen-negative groups. Of all males admitted for PHT, 51.5% were screen positive at age eight (sensitivity, n=84 of total 163 subjects with complete childhood data, positive predictive value (PPV)=10.7%), while the sensitivity among females was 27.1% (n=29 of total 107, PPV=9.0%). Additionally, in both sexes, screen-positive status predicted mood disorders (M: n=21, sensitivity=53.9%, PPV=2.7%, HR 2.81, 95%CI 1.50-5.27, p=.001; F: n=15, sensitivity=30.6%, PPV=4.7%, HR 3.16, 95%CI 1.72-5.81, p<.001), anxiety disorders (M: n=19, sensitivity=52.8%, PPV=2.4, HR 2.67, 95%CI 1.39-5.14, p=.003; F: n=6, sensitivity=42.7%, PPV=1.9%, HR 5.32, 95%CI 1.85-15.32, p=.002) and substancerelated disorders (M: n=29, sensitivity=60.4%, PPV=3.7%, HR 3.67, 95%CI 2.06-6.54, p<.001; F: n=9, sensitivity=37.5%, PPV=2.8%, HR 4.28, 95%CI 1.87-9.77, p<.001). Psychosis was predicted only among males (n=22, sensitivity=56.4%, PPV=2.8%, HR 3.13, 95%CI 1.66-5.89, p<.001).

Psychopathology types and family variables:

Table 1 shows the predictive associations between family variables and the categorical psychopathology scales at age eight and later PHT, according to the univariate and multivariate analyses. When the two family variables and the four psychopathology scales were included in multivariate models (a model including the categorical scales (Table 1) and another model including the linear scales), PHT, among males, was independently predicted by non-intact family structure (p<.001 for both categorical and linear regressions, given in this order), the conduct scale (p=.03 and p=.006), the emotional scale (p=.01 and p=.002) and the self-reported depressive symptoms in the linear regression (p=.008). Among females, PHT was independently predicted by the self-reported depressive scale (p=.02 for both regressions) and the emotional scale in the linear regression (p=.04).

Because of the small number of subjects, linear instead of categorical psychopathology scales were primarily used to analyze the predictive association between childhood psychopathology and specific diagnostic groups (Table 2). Psychosis was independently predicted by the conduct scale among males. Mood disorders were independently predicted by the emotional scale and the self-reported depressive symptoms in both sexes.

Anxiety disorders were independently predicted by the emotional scale among males. Substance-related disorders were independently predicted by non-intact family structure and the conduct scale in both sexes.

Because of the particular importance of early identification of children at risk of psychotic disorders we further examined associations between categorical measures of psychopathology at age eight and later psychotic disorder. Out of 40 males admitted for a psychotic disorder, 32.5% scored above the 90th percentile on the conduct scale (HR 4.35, 95%CI 2.25-8.43, p<.001), 28.2% on the emotional scale (HR 2.84, 95%CI 1.41-5.70, p=.003) and 22.5% on the hyperkinetic scale (HR 2.84, 95%CI 1.35-5.96, p=.006). Among 22 females with psychosis, 27.3% scored above the 90th percentile on the emotional scale (HR 3.44, 95%CI 1.35-8.79, p=.01).

The same associations were significant, when the psychopathology measures were analyzed as linear variables in the univariate analysis (Table 2).

Combinations of psychopathology:

The conduct, attention-hyperactivity, emotional and self-reported depressive psychopathology scales were combined to disentangle the predictive value of pure versus comorbid problems and of adult-versus self-reports. The proportions of subjects with different combinations of psychopathology who had later been treated for a psychiatric disorder are shown in Figure c andd, including the univariate predictive associations for PHT. The strongest predictive association for PHT was found for the comorbid conduct-emotional groups, as 20.9% of the males and 11.5% (PPV) of the females belonging to this group had been treated for a psychiatric disorder during the follow-up period, while the corresponding figures for the reference groups were 3.9% for males and 3.2% for females. Among males, also the attentionhyperactivity group, the conduct group and the emotional group predicted PHT. In additional analysis when the effects of the interactions between the psychopathology types, family structure and parental education level were analyzed on the main outcome PHT, no significant interactions were found.

DISCUSSION

The results of this nationwide population-based study have several findings with implications for the early identification of subjects with psychiatric disorders requiring hospital treatment. Among females, self-reported depressive symptoms at age eight had a strong predictive association with psychiatric outcome, while among males, conduct problems most strongly predicted psychiatric outcomes. However, it was the combination of conduct and emotional problems among both males and females which mainly increased the risk of later PHT.

One out of two males and one out of four females admitted for PHT by the age of 24 were "screen-positives" at age eight, according to either parent or teacher reports indicating possible psychiatric caseness. Accordingly, previous studies have shown that childhood psychopathology predicts especially intensive psychiatric treatment [START_REF] Kim-Cohen | Prior juvenile diagnoses in adults with mental disorder: Developmental follow-back of a prospective-longitudinal cohort[END_REF][START_REF] Weissman | Children with prepubertal-onset major depressive disorder and anxiety grown up[END_REF]. Furthermore, psychiatric problems at age eight increase the risk for later PHT more in males than females, which is in line with the findings from the UKNCDS [START_REF] Done | Childhood antecedents of schizophrenia and affective illness: Social adjustment at ages 7 and 11[END_REF].

When we analyzed combinations of psychopathology scales, the greatest likelihood for PHT was found for children with combined conduct and emotional problems. About 21% of males and 12 % of females with concurrent conduct and emotional problems at age eight were admitted for PHT by age 24, compared to 4% (M) and 3% (F) of the reference group. Previous longitudinal studies have shown that childhood internalizing and externalizing problems are associated with adverse psychiatric outcomes in adulthood [START_REF] Ensminger | Childhood and adolescent antecedents of substance use in adulthood[END_REF][START_REF] Knapp | The Maudsley long-term follow-up of child and adolescent depression: 3. Impact of comorbid conduct disorder on service use and costs in adulthood[END_REF][START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF], including our previous report of males with military call-up data [START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF]. A novel finding in the present study is that the longterm prognosis concerning severe adult disorders requiring PHT, is poorest also among females with comorbid externalizing and internalizing problems in childhood, not only among males.

The developmental gender differences in relation to later psychotic illness have not received the attention this important topic deserves. Intriguingly, among females, only emotional problems had a predictive association with psychosis in early adulthood, while among males, conduct problems was the associated precursor. This is in line with the few existing studies including gender-specific information on childhood psychopathology [START_REF] Done | Childhood antecedents of schizophrenia and affective illness: Social adjustment at ages 7 and 11[END_REF][START_REF] Olin | Assessing the predictive value of teacher reports in a high risk sample for schizophrenia: A ROC analysis[END_REF]. To date, most of the longitudinal birth cohort studies have not reported separate estimates concerning childhood psychopathology for males and females [START_REF] Cannon | Evidence for earlychildhood, pan-developmental impairment specific to schizophreniform disorder: Results from a longitudinal birth cohort[END_REF][START_REF] Jones | Child development risk factors for adult schizophrenia in the British 1946 birth cohort[END_REF][START_REF] Kim-Cohen | Prior juvenile diagnoses in adults with mental disorder: Developmental follow-back of a prospective-longitudinal cohort[END_REF][START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF]. In previous studies, some gender differences have been indicated: neurodevelopmental deficits are more profound among preschizophrenic males than females [START_REF] Welham | The antecedents of schizophrenia: A review of birth cohort studies[END_REF]. Also a life-course-persistent psychopathological deviance has been indicated to associate with psychosis among males, while females often have a later onset of symptoms [START_REF] Welham | The antecedents of schizophrenia: A review of birth cohort studies[END_REF].

Concerning other diagnostic groups treated in hospitals and their impact on childhood psychopathology, the results are largely in line with previous reports. Both mood and anxiety disorders treated in hospitals were predicted by similar problems in childhood [START_REF] Kim-Cohen | Prior juvenile diagnoses in adults with mental disorder: Developmental follow-back of a prospective-longitudinal cohort[END_REF][START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF]. Though attention problems predicted PHT and several diagnoses among males in the univariate analyses, no statistically significant associations were found in the multivariate analyses. This further supports findings from previous longitudinal population based studies were attention problems have been adjusted for other childhood problems [START_REF] Reef | Child to adult continuities of psychopathology: A 24-year follow-up[END_REF]. Substance-related disorders were predicted by conduct problems [START_REF] Elkins | Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse[END_REF][START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF], and non-intact family structure in both sexes [START_REF] Weitoft | Mortality, severe morbidity, and injury in children living with single parents in Sweden: A population-based study[END_REF]. However, a non-intact family may not be seen as a risk per se, but, for example, through the often associated family problems like disadvantageous child-rearing practices, financial problems and psychiatric problems among parents [START_REF] Fergusson | Exposure to single parenthood in childhood and later mental health, educational, economic, and criminal behavior outcomes[END_REF].

Generally, it is considered that children's self-reports of psychopathology, especially depressive symptoms, become more important the older the children get [START_REF] Sourander | Parent-adolescent agreement on emotional and behavioral problems[END_REF][START_REF] Verhulst | Parent, teacher and self-reports as predictors of signs of disturbance in adolescents: Whose information carries the most weight?[END_REF]. In the present study, self-reports were gathered already at the age of eight, which is earlier than in other psychiatric birth cohort studies with outcomes in adulthood [START_REF] Sourander | Who is at greatest risk of adverse long-term outcomes? The Finnish from a boy to a man study[END_REF]. A novel finding is that self-reports of depressive symptoms at age eight show independent predictive associations with later PHT among females, while adult reports remain significant among males. If replicated, this finding indicates that especially girls' depressive symptoms are often not noticed by adults, though it is an important warning sign for possible later adverse outcomes. Also the self-identification of depressive symptoms

The strengths of the sample include the fact that it is nationwide, a follow-up rate of 91%, and the use of a nationwide well-documented register [28,[START_REF] Sourander | Childhood predictors of completed and severe suicide attempts: Findings from the Finnish 1981 birth cohort study[END_REF][START_REF] Tiihonen | Premorbid intellectual functioning in bipolar disorder and schizophrenia: Results from a cohort study of male conscripts[END_REF]. However, several limitations should be considered when interpreting the results of this study. First, interviews were not used to assess childhood psychopathology. Some individual and environmental factors, like family factors, could possibly have affected the level of psychopathology reported in the questionnaires, which could have been corrected with a clinical judgement.

Conversely, the use of brief reports made it possible to obtain a large sample with high a participation rate (97%). Second, though former studies concerning psychotic disorders have shown that the hospital discharge register is diagnostically valid and very accurate in detecting psychoses [28], we do not have data on the diagnostic validity of, e.g., anxiety disorders. However, all Finnish inpatient units are legally obliged to report all discharges to the register, and 97.6% of all registered psychiatric diagnoses are identical with the ones in medical records [START_REF] Keskimäki | Accuracy of data on diagnoses, procedures and accidents in the Finnish hospital discharge register[END_REF]. Third, admission to PHT depends not only on the severity of the disorder, but also on help-seeking patterns and on the health care system. Yet, the legal principles of outpatient and inpatient treatment in mental health are from 1990, and the rate of psychiatric inpatient treatment has remained the same between 1994 and 2007 (6.0 discharges in general and mental hospitals per 1000 adult population [START_REF]Psykiatrian erikoisalan laitoshoito[END_REF]).

Given the burden of severe psychiatric disorders and intensive psychiatric treatment on individuals and society, early identification of these patients is a major challenge for mental health services. Based on our results, we recommend different screening strategies for males and females, when identifying children at risk of later psychiatric disorders requiring PHT. Among males, conduct problems, while among females, anxiety and selfreported depressive problems, have the strongest association with PHT. However, comorbid conduct and emotional problems carry the highest risk of later PHT in both sexes. Moreover, information from multiple sources is emphasized and especially girls' reports of their own internal distress should not be overlooked in screening or clinical assessment. reference (males (M): 69.9%, females (F): 70.6%), conduct-emotional (M: 4.3%; F: 3.5%), conduct-only (M: 5.7%; F: 7.8%), attention (M: 4.0%; F: 5.6%), emotional-only (M: 9.6%; F: 6.7%) and invisible status (M: 6.5%; F: 5.7%). Reported hazard ratios (HR) with confidence intervals (95%CI) are done with univariate Cox's regression analysis.

Fig. 1

 1 Fig. 1 Estimated survival curves for surviving without psychiatric hospital treatment between age 13 and 24 by screening status among males (Fig a, n=2638, 29.6% screen positive) and females (Fig b, n=2554, 12.6% screen positive) and by different combinations of psychopathology among males (Fig c, n=2544) and females (Fig d, n=2471). The psychopathology combinations:

Table 2 .

 2 Predictive associations between family structure and psychopathology scales at age eight, and psychiatric hospital treatment of different diagnostic groups between age 13 and 24. The univariate and multivariate analyses were done with Cox's regression analysis. a

Table 2 .

 2 Predictive associations between family structure and psychopathology scales at age eight, and psychiatric hospital treatment of different diagnostic groups between age 13 and 24. The univariate and multivariate analyses were done with Cox's regression analysis. a

	Males

.18 (1.11-4.29) .02

				1.68 (0.80-3.53)	.17	2.5 (10) 1.36 (0.68-2.72)	.39	1.23 (0.61-2.51)	.56
	Parental education level
	Upper secondary	1.6 (15)				1.4 (13)
	Lower	1.4 (23) 0.85 (0.45-1.63)	.63	0.71 (0.36-1.41)	.33	2.2 (36) 1.53 (0.81-2.89)	.19	1.40 (0.72-2.72)	.32
	Linear psychopathology scales c
	Conduct scale	(2601) 1.40 (1.10-1.79)	.007	1.40 (0.97-2.03)	.07	(2548) 1.29 (1.08-1.54)	.005	1.17 (0.91-1.50)	.21
	Attention scale	(2585) 1.22 (0.92-1.61)	.17	0.80 (0.53-1.22)	.31	(2525) 1.23 (0.99-1.52)	.06	1.01 (0.75-1.36)	.95
	Emotional scale	(2595) 1.57 (1.25-1.97)	<.001	1.44 (1.12-1.86)	.005	(2528) 1.41 (1.13-1.77)	.002	1.24 (0.97-1.58)	.09
	Self-report of depressive symptoms	(2658) 1.51 (1.20-1.89)	<.001	1.35 (1.05-1.74)	.02	(2574) 1.42 (1.14-1.76)	.002	1.29 (1.02-1.64)	.03

ACKNOWLEDGEMENTS

The study has been supported by the Medical Society of Finland (Finska Läkaresällskapet), the Finnish Foundation for Paediatric Research (Lastentautien tutkimussäätiö) and the Wilhelm and Else Stockmann Foundation. The authors wish to thank Ms Jarna Lindroos for secretarial assistance. The authors declare that they have no conflict of interest.

Abbreviations: HR, hazard ratio; CI, confidence interval. a Bold face indicates a statistically significant association at p<.05. b Subjects who had not been admitted for psychiatric hospital treatment between age 13 and 25 were used as reference group in Cox's regression analysis.