Draft guideline on the development of new medicinal products for

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21 July 2016
CHMP/EWP/18463/2006 Rev. 1
Committee for Medicinal Products for Human Use (CHMP)
5
Guideline on the development of new medicinal products
for the treatment of Ulcerative Colitis
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Draft
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Draft agreed by Efficacy Working Party
Adopted by CHMP for release for consultation
End of consultation (deadline for comments)
Agreed by Efficacy Working Party
04 October 2006
16 November 2006
31 May 2007
September 2007-January
2008
Adoption by CHMP
24 January 2008
Date for coming into effect
01 August 2008
Agreed by Gastroenterology Drafting Group
Adopted by CHMP for release for consultation
Start of public consultation
End of consultation (deadline for comments)
March 2016
21 July 2016
1 August 2016
31 January 2017
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This guideline replaces' guideline on the development of medicinal products for the 8 treatment of
9
ulcerative colitis’ (CHMP/EWP/18463/2006)
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Comments should be provided using this template. The completed comments form should be sent to
[email protected]
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Keywords
Inflammatory bowel disease, Crohn’s disease, medical treatment,
clinical trials, study design, study endpoints, children, adults
30 Churchill Place● Canary Wharf ● London E14 5EU● United Kingdom
Telephone +44 (0)20 36606000 Facsimile +44 (0)20 3660 5555
Send a question via our website www.ema.europa.eu/contact
An agency of the European Union
© European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged.
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Guideline on the development of new medicinal products
for the treatment of Ulcerative Colitis
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Table of contents
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Executive summary ..................................................................................... 3
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1. Introduction (background) ...................................................................... 3
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2. Scope....................................................................................................... 3
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3. Legal basis and relevant guidelines ......................................................... 3
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4. Criteria and Standards for Patient selection ............................................ 4
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4.1. Definition and specification of the disease................................................................ 4
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4.1.1. Active UC ......................................................................................................... 4
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4.1.2. Steroid dependency ........................................................................................... 4
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4.1.3. Refractory disease ............................................................................................. 4
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4.1.4. UC in remission ................................................................................................. 5
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5. Possible indications/treatment goals ...................................................... 5
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6. Assessment of efficacy ............................................................................ 5
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6.1. Methods to assess efficacy criteria .......................................................................... 5
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6.1.1. General Aspects ................................................................................................ 6
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7. Study design............................................................................................ 7
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7.1. Pharmacology studies ........................................................................................... 7
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7.1.1. Pharmacokinetics............................................................................................... 7
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7.1.2. Pharmacodynamics ................................................ Error! Bookmark not defined.
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7.1.3. Interactions ...................................................................................................... 7
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7.2. Therapeutic studies .............................................................................................. 7
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7.2.1. Dose finding studies ........................................................................................... 7
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7.2.2. Confirmatory studies .......................................................................................... 8
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8. Safety aspects ....................................................................................... 12
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8.1. Specific effects ................................................................................................... 12
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8.2. Long-term effects ............................................................................................... 12
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8.3. Studies in special populations .............................................................................. 12
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8.3.1. Studies in paediatric patients ............................................................................ 12
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8.3.2. Patients with acute sever colitis ......................................................................... 15
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8.3.3. Patients with pouchitis ..................................................................................... 15
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8.3.4. Patients with extra-intestinal manifestations ....................................................... 16
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9. Risk management plan .......................................................................... 16
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Guideline on the development of new medicinal products for the treatment of
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Executive summary
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This is the 1st revision of the Guideline on the development of new medicinal products for the
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treatment of UC.
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The main aim of this 1st revision is to update the guidance on the design of studies in adult patients,
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especially on potential claims, primary and secondary endpoints and comparators. It is also intended to
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give further guidance with regards the possibility for extrapolation from adults, or the need to generate
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separate data in children and to give recommendations regarding the exploration of PK/PD in
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paediatric drug development.
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1. Introduction (background)
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UC is a chronic, relapsing inflammatory bowel disease affecting the colon. The prevalence is estimated
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to be 70-500 cases per 100.000 with peak age of onset between 15 and 25 years. In 15% of cases UC
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is diagnosed in childhood and may present before school age. The disease involves the rectum and
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may extend continuously proximally to involve part of or the entire colon. The mainstay of therapy for
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mild to moderate UC is 5-aminosalicylic (5-ASA) agents. These agents are effective at inducing
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remission in UC and in maintaining remission in UC. The majority of patients with moderate to severe
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active UC benefit from topical, oral or parenteral glucocorticosteroids. Remission, however, cannot be
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maintained with steroids. Azathioprine (AZA) or mercaptopurine (MP) has been employed as
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glucocorticoid-sparing agents in patients unable to be weaned from glucocorticoids. Anti-tumour
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necrosis factor α (TNF) agents and integrin inhibitors are indicated for the treatment of UC patients
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refractory to standard treatment (as previously described). Surgery with colectomy is curative but can
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be associated with significant morbidity and is thus reserved for acute severe (fulminant) colitis or
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resistant cases and in some cases as cancer prevention. Intestinal continuity can be restored by
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construction of an ileal pouch-anal pouch anastomosis.
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Pouchitis is an inflammation of the ileal pouch, occurring in up to 20-30% of patients with an ileal
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pouch-anal anastomosis. The risk of colorectal cancer is increased in patients with extensive disease
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and surveillance is usually introduced after 8-10 years of disease duration with regular colonoscopies.
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Extra-intestinal manifestations of UC include primary sclerosing cholangitis, as well as eye, joint and
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skin manifestations.
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2. Scope
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Guidance is provided on the EU regulatory position on the main topics of the clinical development of
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new medicinal products in the treatment of patients with UC. This document is aimed to replace the
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‘Guideline on the development of new medicinal products for the treatment of UC’
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(CHMP/EWP/18463/2006).Generic drug development is not covered.
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The current revision concerns a major update of the guidance document with regards to the issues
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mentioned in the executive summary above.
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3. Legal basis and relevant guidelines
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This Guideline should be read in conjunction with the introduction and general principles of Annex I to
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Directive 2001/83/EC, as amended, and all other relevant EU and ICH guidelines. These include, but
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are not limited to:
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•
Points to Consider on Multiplicity Issues in Clinical Trials (EMA/CPMP/EWP/908/99).
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•
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•
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Reflection Paper on the regulatory guidance for the use of Health-Related Quality of Life (HRQL)
measures in the evaluation of medicinal products (CHPM/EWP/139391/04)
•
92
93
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99).
Guideline on the role of pharmacokinetics in the development of medicinal products in the
paediatric population (EMEA/CHMP/EWP/147013/2004 Corrigendum)
•
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Guideline on Risk Management Systems for Medicinal Products for Human Use
(EMEA/CHMP/96268/2005).
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4. Criteria and Standards for Patient selection
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4.1. Definition and specification of the disease
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4.1.1. Active UC
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UC is a chronic, inflammatory disease of the large intestine and rectum characterised by episodes of
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increased stool frequency and bloody diarrhoea. Patients complain of pain (abdominal cramps),
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urgency and bloody diarrhoea. The diagnosis of UC should be based on patient signs and symptoms
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(diarrhoea and rectal discharge of blood and/or pus), endoscopic findings (continuous oedema,
102
friability, granularity and ulcerations in colorectal mucosa), and histological findings (crypt
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distortion/abscess, ulceration). Infectious causes of colitis and malignancy must be ruled out.
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Depending on the extent of disease, patients can be classified (according to the Montreal classification)
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as having 1) ulcerative proctitis involving only the rectum (E1), 2) left sided UC involving the
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colorectum distal to the splenic flexure (E2) and 3) extensive UC (E3) involving the colon proximal to
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the splenic flexure (includes pancolitis). Up to 30% of patients with distal disease will experience
108
proximal extension with time. Depending on the disease activity, patients can be classified as having
109
mild, moderate or severe disease activity according to one or more measures of disease severity.
110
Patients with acute severe UC not responding to steroids represent a special subgroup.
111
4.1.2. Steroid dependency
112
In line with current published European guidelines (European Crohn's and Colitis Organisation (ECCO)),
113
patients exhibiting response to steroids who
114
i.
115
are unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of
starting steroids, without recurrent active disease, or
116
ii.
have a relapse within 3 months of stopping steroids
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can be considered steroid dependent.
118
4.1.3. Refractory disease
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Patients who continue to have active disease despite the use of corticosteroids in an adequate dose
120
and for an adequate time period are defined as being steroid refractory. According to published
121
European guidelines (ECCO), patients who have active disease despite prednisolone up to 0.75
122
mg/kg/day over a period of 4 weeks can be characterised as having steroid refractory disease. Patients
123
are refractory to azathioprine/6-mercaptopurine if they continue to have active disease despite at least
124
3 months of treatment with a sufficient dose.
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4.1.4. UC in remission
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Patients with mucosal healing (MH) (for the purpose of this guideline MH is defined as absence of
127
macroscopic signs of active inflammation as judged by endoscopy) who have no or very mild
128
symptoms and signs are considered in remission. The precise definitions depend on the instruments
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used to assess mucosal inflammation and symptoms (please see below).
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5. Indications/treatment goals
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In order to obtain an indication for “treatment of active ulcerative colitis”, efficacy in both “induction of
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remission” as well as “maintenance of remission” should be demonstrated
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Depending on the properties of the drug (i.e. not suitable for long term treatment or not suitable for
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acute treatment) separate indications for “induction of remission” or “maintenance of remission” may
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be granted.
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The treatment of active disease/induction of remission, and the treatment for maintenance of
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remission/prevention of relapse may be studied either in separate trials or trials that combine induction
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treatment with maintenance treatment. While a “treat through” design may be acceptable the design
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of the study will have implications for the indications that can be claimed. Only separate investigation
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of induction of remission and maintenance of remission would allow claims for separate indications for
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induction and maintenance of remission.
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Other claims such as steroid sparing and improvement in quality of life should not form a part of the
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indication, but may be included in other relevant section(s) of the prescribing information. However,
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the ultimate treatment goal for all patients with UC is steroid-free clinical and endoscopic remission.
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6. Assessment of efficacy
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6.1. Methods to assess efficacy criteria
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New drugs intended for the treatment of UC are expected to provide symptomatic relief to the patient
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based on a documented effect on the inflammatory process. Apart from demonstrating that the
149
symptomatic effect is indeed related to a positive effect on the disease process the latter element is
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considered essential as there is evidence that lack of control of inflammation even in the presence of
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control of symptoms is correlated with poor long term outcome.
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Symptomatic relief should be evaluated by patient related outcomes (PRO). There are a number of
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clinical indices, e.g. SCCAI (simple clinical colitis activity index) mainly including patient reported
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symptoms. Whereas these may be used provided that they are adequately validated, this guideline
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recommends the further development and validation of PRO instruments for the use as primary
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outcome parameter in clinical trials in UC. Such an instrument should include clinically important signs
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and symptoms of UC, e.g. increased stool frequency and rectal discharge of blood. An instrument to be
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used as primary outcome measure in pivotal clinical trials in UC should be completely and rigorously
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validated.
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Whereas symptomatic relief is best evaluated by patient reported outcomes, the effect on the
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inflammatory process as such should be evaluated directly by endoscopy. A number of different indices
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have been used for grading endoscopic disease activity. UCEIS (UC endoscopic index of severity) and
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the endoscopic part of the Mayo score appear to be the best, albeit not fully, validated scores.
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A significant effect on both aspects of the disease is required (co-primary endpoints). Composite
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indices including both symptoms and MH, such as the Mayo Clinic index have been used in several
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clinical trials. The use of this index may be justified, however, as previously mentioned, an effect on
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both the patient related sub-score and the endoscopic score is expected. It has to be stressed that the
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total Mayo score including physician’s global assessment is not of primary interest.
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Surrogate markers of inflammation, such as CRP and faecal calprotectin are considered supportive but
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cannot replace direct endoscopic evaluation of inflammation.
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6.1.1. General Aspects
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6.1.1.1. Primary endpoint
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Achieving/maintaining remission free of steroids is an appropriate primary end-point. In patients
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receiving systemic steroids these should be tapered according to predefined schedules. For induction
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studies of short duration requiring early evaluation of efficacy a low dose of steroids may be acceptable
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provided that the dose is clearly justified and pre-specified.
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Remission should be defined and justified according to the instruments used for evaluating signs and
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symptoms and inflammation, respectively. E.g. when mucosal inflammation is evaluated by the Mayo
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sub score, a score of 0 or 1 may be used for defining endoscopic healing. Whereas the more stringent
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definition is preferred, the less stringent definition could be acceptable, based on the
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pharmacodynamic (PD)-properties of the investigational compound and/or the patient characteristics
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(e.g. severity).Adjudication of endoscopic evidence of activity should be performed, preferably by
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central reading of the examinations. If decentralised reading of examination is performed,
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standardization of reading should be convincingly demonstrated. Correspondingly, when clinical
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symptoms are evaluated using the clinical part of the Mayo score, a score of 0 or 1 may be used to
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define symptomatic remission.
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Irrespective of scale used, the definition of remission should encompass cessation of rectal bleeding.
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As outlined above, symptomatic remission and MH should be considered co-primary endpoints.
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However, as listed below, achieving both symptomatic remission and MH (for the individual patient) is
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considered an important secondary endpoint. The timing of measuring the primary endpoint depends
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on the aim of the treatment (please see below) as well as the pharmacodynamic properties of the test
192
drug.
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6.1.1.2. Secondary endpoints
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•
Patients achieving both MH and symptomatic remission
195
•
Patients achieving response. Response should be defined according to the instruments used for
196
197
evaluating symptoms and inflammation, respectively.
•
Patients achieving remission defined differently from the primary evaluation (if the less stringent
198
evaluation regarding MH is chosen, the more stringent should be used in the secondary evaluation,
199
and vice-versa)
200
•
Numerical evaluations of the symptom score, and of MH
201
•
Histological evaluation of mucosal inflammation, including number of patients achieving histological
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203
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normalisation
•
Patients achieving MH, judged endoscopically, as well as combined clinical, serological
(=normalisation of CRP and/or calprotectin) and histological remission
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•
Time to remission;
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•
Time to response;
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•
Laboratory measures of inflammation (e.g. CRP, faecal calprotectin);
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•
Validated QoL measurement (please see EMA Reflection Paper on the regulatory guidance for the
209
use of Health-Related Quality of Life (HRQL) measures in the evaluation of medicinal products),
210
e.g., inflammatory bowel disease questionnaire (IBDQ);
211
•
Steroid sparing effect such as: Proportion in steroid-free remission;
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•
Reduction in number of colectomies.
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In patients who are steroid dependent, withdrawal of the steroids may be the objective. The primary
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endpoint should be the number of patients in clinical and endoscopic remission in whom steroids could
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be withdrawn. Procedures for withdrawal (e.g., tapering schedules) should be predefined.
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Even though separate trials in mild to moderate and moderate to severe are recommended (due to
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differences in comparators), it is recommended to use a stratified randomisation according to disease
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activity as judged by mucosal inflammation, e.g. mild, moderate and severe. The response with regard
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to intestinal and extra intestinal symptoms and findings should be measured individually in all patients
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to determine possible predictors to response and failure. Efficacy should be analysed according to
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prospectively defined disease and patient characteristics. Mode of delivery into the intestines for locally
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acting drugs should be taken into account.
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7. Study design
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7.1. Pharmacology studies
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7.1.1. Pharmacokinetics
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The pharmacokinetic properties of the medicinal product should be thoroughly investigated in
227
accordance with relevant guidelines regarding interactions, special populations (elderly and paediatric,
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renal and hepatic patients), and specific quality aspects (locally applied drugs, proteins and monoclonal
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antibodies).
230
7.1.2. Interactions
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Interaction studies should be performed in accordance with the relevant guidelines. Efficacy and safety
232
implications of concomitant drugs likely to be co-administered in clinical practice (e.g. glucocorticoids,
233
immunosuppressants) should be evaluated.
234
7.2. Therapeutic studies
235
7.2.1. Dose finding studies
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For the dose response ICH E4 guidance Dose-Response Information to Support Drug Registration
237
should be considered. Evaluation of multiple doses is recommended. Placebo controlled, randomized,
238
double blind and parallel group design is recommended. Duration of the phase II dose finding study
239
depends on the indication sought (induction of remission and/or maintenance of remission) as well as
240
pharmacodynamic properties/safety profile/mode of action of the drug and the chosen endpoints but
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should generally not be shorter than 6-8 weeks.
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7.2.2. Confirmatory studies
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7.2.2.1. Treatment of active disease/Induction of remission
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7.2.2.1.1. Design elements
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In active UC, the design should be a randomised double blind parallel group comparison. In the
246
absence of withdrawal of consent, clinical deterioration or failure to improve (according to pre-defined
247
definitions for treatment failures), treatment under double-blind conditions should continue until the
248
completion of the active treatment period. In the absence of withdrawal of consent, all patients should
249
complete the pre-specified follow-up period for the study. Escape procedures for non-responders
250
should be included in the protocol (especially when a placebo-control is included in the trial), which
251
should secure a meaningful comparison of the treatments. Whereas unavoidable from a ethical point of
252
view, a high number of patients receiving rescue medication may be undesirable from a methodological
253
point of view and may be particular problematic in non-inferiority studies where assay sensitivity may
254
be lost.
255
In general, in order to demonstrate durability of response, active treatment should continue for 8
256
weeks. However, based on the pharmacokinetic and pharmacodynamic properties (including mode and
257
speed of onset of action) of the new compound, a shorter/longer duration may be justified. Longer
258
study duration may be justified depending on the onset of action of the drug. However in order to
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provide a useful intervention for acute active disease, symptom control is expected within 4 weeks. An
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appropriate follow-up period off therapy is recommended to see if patients who are in remission at the
261
end of treatment remain in remission at the end of follow-up, unless the patients are continuing the
262
treatment in a re-randomised or continued maintenance study. Patients on steroids at entry should
263
have their dose tapered according to predefined tapering schedules. Obtaining steroid-free remission
264
should be the goal of therapy. .As previously stated, if efficacy is evaluated at an early time point, a
265
low dose of steroids in remitters may be acceptable provided that this is adequately justified and pre-
266
specified. In case efficacy is evaluated at multiple time points, the primary time point for analysis
267
should be pre-specified and justified (please refer to Points to Consider on Multiplicity Issues in Clinical
268
Trials). Evaluation of rebound after tapering of steroids should be evaluated.
269
7.2.2.1.2. Patient selection/target population
270
Failed prior therapies and on-going treatment should also be taken into account.
271
Patients included should have evidence of active disease as outlined in section 4. Minimal levels of
272
symptoms and mucosal inflammation needed for inclusion should be defined. Degree and extent of
273
mucosal inflammation should be documented by recent visualisation of the gastrointestinal tract, by
274
endoscopic examination.
275
As there are currently no fully validated PROs, a score of 6-12 in the clinical part of the Mayo score
276
may be used as an inclusion criterion but patients included must also have a certain minimal level of
277
mucosal inflammation (e.g. a score ≥ 2 when using the endoscopic part of the Mayo score).
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The choice of study population should reflect the proposed indication. Patients included should be well
279
characterised especially as regards disease extent (proctitis, left-sided or extensive), duration, disease
280
activity, prior treatment and smoking status. The minimum time from diagnosis should be at least 3
281
months at inclusion. Shorter duration of disease has to be justified and care must be taken to avoid
282
inclusion of patients with diarrhoea due to other causes e.g. infections and Crohn’s disease.
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7.2.2.1.3. Choice of endpoints
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Please refer to “General Aspects” above. The primary endpoint should be steroid free remission.
285
7.2.2.1.4. Choice of comparator
286
The choice of comparator will depend on the indication for which the drug is being developed. In order
287
to support a first line indication in the treatment of active UC, it is necessary to demonstrate that the
288
drug has either the same or an improved risk/benefit profile as the standard of care. Therefore, clinical
289
trials aiming at supporting a first line indication should always include comparison with the accepted
290
first line treatment.
291
treatment, it is critical that assay sensitivity can be demonstrated, ideally by adding a placebo arm
292
(ref. ICH E10).
293
In order to support an indication for add-on to established therapy, the drug should be compared with
Unless the study is aiming at demonstrating superiority against an existing
294
add-on placebo. For a second-line indication in patients with insufficient response to established
295
therapy, it is advised that the established therapy is continued and placebo or experimental therapy is
296
added on. Failure of the background treatment should be clearly defined. In this respect, merely
297
having previously been exposed (without documentation of insufficient response) to one or more first
298
line drug is not considered sufficient.
299
First line treatment (treatment naïve patients):
300
Mild to moderate disease
301
For mild to moderate active UC, oral and/or topical 5-ASA (depending on the extent of the disease) is a
302
well-established safe and efficacious treatment for both induction and maintenance of remission..
303
Superiority against the comparator is the ideal requirement. Non-inferiority against 5-ASA is also
304
acceptable. However, the option of a 3-arm trial with placebo and an active comparator, where the
305
latter would serve as an internal reference (not requiring formal non-inferiority) may be acceptable in
306
certain circumstances, e.g. when the size of a non–inferiority trial is impractical.
307
Moderate to severe disease
308
Systemic corticosteroids are considered a well-established safe and efficacious treatment in this
309
setting. Consequently, for a first line indication for induction of remission in moderate to severe UC,
310
any new treatment should demonstrate non-inferiority (or superiority) against systemic corticosteroids.
311
Patients included in a study of this kind cannot be on steroids at entry.
312
Second line treatment (treatment experienced patients)
313
In patients who have symptomatic as well as objective active disease despite standard treatment such
314
as 5-ASA, thiopurines and/or corticosteroids, it is clinical practice to continue standard treatment
315
(except for corticosteroids, which generally should be discontinued at the earliest time point possible,
316
depending on the obvious side effects already present, and the duration of the pre-treatment) and to
317
add additional treatments. Consequently, placebo controlled add-on studies is an acceptable option in
318
this setting. While formal (non-inferiority/superiority) comparison with TNF-inhibitors is not considered
319
mandatory, it is encouraged. In case of targeting TNF-experienced patients, add-on, placebo-controlled
320
studies are considered acceptable.
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7.2.2.2. Maintenance of remission/Prevention of relapse
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7.2.2.2.1. Design elements
323
The efficacy of maintenance treatment should be established by means of placebo-controlled trials.
324
Patients in remission without any treatment should be treated with placebo or test drug. Patients who
325
are presently on the test drug should be randomised to continuing the test drug or switching to
326
placebo. Patients in remission while on maintenance therapy may receive placebo or test drug as add
327
on therapy or may be randomised between continued maintenance therapy (or placebo) and the
328
experimental compound only.
329
In the absence of clinical deterioration (according to pre-defined definitions for treatment failures) and
330
withdrawal of consent, treatment under double-blind conditions should continue until the completion of
331
the study period. For handling of missing data please refer to Guideline on Missing Data in
332
Confirmatory Clinical Trials.
333
The treatment period should be aimed at a minimum of 12 months.
334
7.2.2.2.2. Patient selection/target population
335
Patients who are in steroid free remission (as defined above) are eligible for inclusion into the trials. In
336
lack of properly validated PROs a score of 0-1 in the clinical part of the Mayo score may be used as an
337
inclusion criterion but patients included must also have an evidence of MH (e.g. a score <2 or 0 when
338
using the endoscopic part of the Mayo score). This should be documented by visualisation of the
339
gastrointestinal (GI) tract by endoscopic examination.
340
Trials combining induction treatment and maintenance treatment should preferably only enter patients
341
that have achieved remission (in either the trial drug or comparator group), into the maintenance
342
phase. Responders may be included in the maintenance phase as it is considered relevant to study if
343
continued treatment in responders may eventually lead to remission. However, if the intended claim is
344
“maintenance of remission”, the primary analysis should be based on the remitters only. Furthermore,
345
in order to claim maintenance of remission, a re-randomisation between phases is considered
346
necessary. As mentioned in section 5, a treat-through design (without re-randomisation) may be
347
acceptable and will provide evidence of the effect of long-term treatment. However, true maintenance
348
of efficacy cannot be supported by such a trial and consequently such a trial cannot support a claim for
349
“maintenance of efficacy”.
350
For combined studies aiming at supporting general treatment indication, it is required that statistically
351
and clinically significant results are obtained for both phases of the trial.
352
Choice of design may be influenced by differences in dosage for induction and maintenance,
353
respectively.
354
7.2.2.2.3. Choice of endpoints
355
It is recommended that the primary end-point should be steroid free remission maintained without
356
surgery throughout at least 12 months. Time to event analysis is only consideres supportive as just
357
pronlonging time to relapse without decreasing the end of study risk is not considered a relevant
358
benefit. As secondary endpoints, reduction in surgery, quality of life (as measured by validated indices
359
such as IBDQ, EuroQol-5D, SF36) and time to relapse could be considered. Severity of relapse should
360
also be considered.
361
Relapse should be defined a priori, including the need for deterioration of a certain degree of
362
symptoms and/or inflammatory markers, and final confirmation with endoscopy (on demand). Patients
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with relapse undergoing re-treatment, or leaving the study with treatment outside the protocol should
364
nevertheless undergo the full period of planned follow-up. Efforts should be made to obtain all
365
relevant endpoints in all patients irrespective of treatment adherence.
366
Please also refer to “General Aspects” above.
367
7.2.2.2.4. Choice of comparator
368
The choice of comparator depends on the indication for which approval is being sought. For a first line
369
indication of maintenance of remission, the efficacy of maintenance therapy in this patient population
370
should be determined by placebo-controlled trials if ethically justifiable. In addition, for the refractory
371
population, comparative studies using immunosuppressive therapies such as azathioprine and
372
mercaptopurine (MP) or TNF-inhibitors as comparators are recommended.
373
7.2.2.3. Previous and concomitant treatment
374
Patients with UC usually receive maintenance treatment and should in general be allowed to continue
375
with these during a trial in active disease as background therapy. The duration and dose of
376
concomitant treatment prior to inclusion should be defined. For 5-ASA, a stable dose for > 2 weeks is
377
appropriate for induction studies and > 4-6 weeks for maintenance studies. Treatment with AZA/MP
378
requires stable doses for at least 3 months.
379
When concomitant treatment is not to be allowed, adequate washout period should be defined. For
380
newer immunomodulating agents, that may have prolonged action, adequate washout period based on
381
the pharmacodynamic effect of these agents should be ensured.
382
For a refractory population, it should be ensured that patients have received optimal treatment before
383
randomisation. A minimum duration and dose of previous (baseline) medication should be defined. For
384
a second line indication in moderate and severe disease, this would usually imply corticosteroid use at
385
baseline. History of previous use of corticosteroids and 5-ASA is of little relevance, as most patients
386
diagnosed with UC will have used these medications at some time during the course of their disease.
387
Such previous use should not be confused with refractoriness. Corticosteroid dependency should be
388
defined as previously specified. Intolerance should also be defined by minimum criteria of severity, e.g.
389
previous mild and resolved side effects to corticosteroids that did not lead to discontinuation of the
390
treatment would not classify as patient being intolerant to corticosteroids. Refractoriness to AZA/MP
391
requires at least 3-6 months of treatment without improvement. Intolerance to AZA/MP should be
392
clearly defined and documented.
393
Tapering schedules for glucocorticoids during trials should be standardised. Usually tapering can be
394
done with 2.5 to 5 mg/week in induction studies. Too rapid tapering is to be avoided. As noted above,
395
patients who have not been tapered before or within the induction phase should have their steroids
396
tapered within 12 weeks after entering the maintenance phase. If bridging to AZA/MP is the purpose of
397
the trial, the tapering of the investigational drug should be over 3 months at least.
398
Concomitant treatment with topical treatment in extensive disease may influence the endoscopic
399
findings with sigmoidoscopy and thus it would be acceptable not to allow this kind of treatment if the
400
prime purpose is to evaluate the effect of oral or systemic therapy. However, in order to reflect the
401
real life use of compounds, ideally, both treatment modalities (cessation and continuation of local
402
treatment) should be investigated. Antibiotics should normally be excluded and in severe disease, anti-
403
cholinergic, anti-diarrhoeal, NSAID and opioid drugs should not be allowed as they may contribute to
404
worsening of the relapse.
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8. Safety aspects
406
8.1. Specific effects
407
Identified adverse events should be characterised in relation to the duration of treatment, the dosage,
408
the recovery time, age and other relevant variables. A major category of products used in the
409
treatment of UC acts as immunomodulators. Therefore special attention should be given to the
410
possibility of occurrence of serious infections, autoimmune diseases and the tumour
411
facilitating/inducing potential of these products. As UC affects young women of childbearing potential,
412
special attention is warranted in this population.
413
8.2. Long-term effects
414
Given the potentially long-term use of drug therapy in UC, data on a large and representative group of
415
patients for a sufficient period of time should be provided. The administration of new biologicals (e.g.,
416
cytokines, anti-cytokines, monoclonal antibodies) may trigger the development of antibodies.
417
Therefore, whether binding-antibodies and/or neutralising antibodies against these products are
418
developed and the impact of this on the long-term efficacy and safety of the product should be
419
investigated.
420
Concomitant use of immunosuppressants in add-on studies may increase the risk for serious adverse
421
events. It is important to register all use of these agents in trials with new immunological treatments.
422
Furthermore, it is important to get information on re-treatment outcomes even after a longer time
423
interval without treatment with a specific drug.
424
8.3. Studies in special populations
425
8.3.1. Studies in paediatric patients
426
Ulcerative colitis is similar in adult and paediatric patients in terms of overall disease pathology and
427
progression and possible treatment targets. However, paediatric forms of IBD are characterised by a
428
more complicated disease course with higher inflammatory activity and higher need for corticosteroids
429
and immunosuppressive therapy. Subsequently children have a higher cancer risk, longer duration of
430
disease, severity or extension of disease compared with adult-onset UC.
431
UC is rare in children below 10 years of age and younger children may develop a different disease
432
phenotype compared with adolescents or adults. The clinical development program should include
433
children from 2 years of age and older unless there are significant safety concerns or signals
434
(occurrence of significant adverse events in juvenile animals or adults or additional immune deficiency)
435
that preclude the inclusion of certain age groups, or unless there is evidence that the product is not
436
likely to be effective or beneficial in certain age groups. Younger children should be genetically tested
437
for known immunological defects and in- or excluded depending on the defect.
438
Due to marginal differences to adult disease inclusion of adolescents with UC into trials with adults can
439
be considered.
440
In general patients with moderate to severe disease activity should be included to enable
441
demonstration of sufficient treatment response.
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8.3.1.1. Extrapolation of data
443
Based on similarity of the disease in adults and in children, extrapolation of efficacy or safety should be
444
considered in order to spare children from unnecessary trials. Application of extrapolation approach
445
may result in a reduction in the amount of data required and/or obviate the need for a formal efficacy
446
trial. An extrapolation plan for paediatric development should be constructed where relevant,
447
addressing the identified knowledge gaps and defining the amount of new data needed ( modelling
448
and simulation, size of trial population, focus on subpopulations or certain age groups only,
449
exploratory/confirmatory design of the study, randomised withdrawal, single-arm or uncontrolled
450
trial…). Usually, extrapolation has to be based at least on efficacy and safety established in adults and
451
paediatric pharmacokinetic and pharmacodynamic data (including the PK-PD and exposure-response
452
relationship).
453
To justify and develop the extrapolation plan, the following factors will need to be considered carefully
454
on a case by case basis:
455
•
456
Whether the substance belongs to a well-studied pharmacological class for which several
substances have already been granted a paediatric indication
457
•
Whether a comprehensive amount of data has already been collected in adults with UC
458
•
Whether a safe dose in children has been identified for the same medicinal product for other
459
diseases.
460
Age, body weight, growth and sexual maturation should be taken into account for specification of the
461
extrapolation plan.
462
Extrapolation assumptions should be confirmed by re-evaluation of the extrapolation concept during
463
development and by post-authorisation collection of real world safety and effectiveness data.
464
8.3.1.2. Pharmacokinetic and dose finding studies in paediatric patients
465
It is well known that age-related differences in PK may be very large and non-linear, especially when
466
inclusion of the youngest age groups is considered. As explained in more detail in the Guideline on the
467
role of the pharmacokinetics in the development of medicinal products in the paediatric population
468
(EMEA/CHMP/EWP/147013/2004 Corrigendum) in the paediatric studies the starting dose per age or
469
weight group and final dose should be selected taking into account all available PK, PD or other
470
(preliminary) data from adults and/or children. In contrast to the PK Guideline it is preferred to apply
471
population PK modelling on the basis of all available data, because this approach allows for an
472
extensive covariate analysis in which the influence of weight, age and other covariates is quantified.
473
The results of this covariate analysis can be used in case a certain exposure (AUC or Ctrough) for
474
instance from adults is aimed for, to identify whether different mg/kg doses per age group may be
475
needed to define to reach the same exposure across the entire paediatric age range, given the fact
476
that the PK may change in a non-linear manner with weight.
477
In addition to the optimisation of posology for subgroups in which the exposure differs from the overall
478
study population and/or is more difficult to predict (i.e. the lower part of an age range), it is
479
emphasized here that particular attention should be paid to the entire age range including the
480
extremes of age receiving the specific product. In addition to the PK Guideline dose adjustments
481
should be allowed in case of sub-target trough or AUC levels to adjust for remaining (inter individual)
482
variability, as there is increasing evidence in adults that precision based dosing may increase efficacy
483
of treatment. Also recommendation on the need for individual dosing and dose adjustment in case of
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sub-target trough or AUC levels in non-responders should be made based on the results obtained
485
during studies.
486
8.3.1.3. Efficacy in paediatric patients
487
Studies in children should aim for achieving remission without side effects on growth and maturation.
488
Remission should be defined as clinical remission accompanied by endoscopic MH. Clinical remission
489
and endoscopic MH should be used as co-primary endpoints.
490
Clinical response alone in children is not considered acceptable as primary endpoint in respect of the
491
longevity of the disease in this age group and colectomy with an ileo-anal pouch as alternative.
492
For induction/ maintenance trials representative changes in mucosal appearance are expected to be
493
evaluated, therefore endoscopy is required.
494
Endoscopic MH should be assessed by the Mayo score (score of 0, or ≤1). Because a validated
495
paediatric PRO (pPRO) for the evaluation of symptoms is not currently available, for the time being,
496
the use of the PUCAI as a surrogate for symptomatic remission is considered acceptable. Clinical
497
remission can therefore be defined as PUCAI<10 points.
498
The primary endpoint of maintenance trials should be sustained relapse-free corticosteroid-free
499
remission (defined as maintaining both, symptomatic clinical remission, and endoscopic MH).
500
In trials when endoscopy is waived, the primary outcome measures should reflect the percentage of
501
patients achieving or maintaining corticosteroid-free remission. Due to the sufficient amount of
502
validation data available with good results, the PUCAI score can be used in such a situation, with
503
remission defined as a PUCAI score of <10 points.
504
8.3.1.4. Strategy and design
505
As stated previously extrapolation can facilitate paediatric development and may result in a reduction
506
in the amount of data and/or change in study design required in certain age groups (see 8.3.1.1.). In
507
situations where extrapolation of efficacy is not possible, the parallel group design provides the most
508
robust evidence for efficacy and safety and is the preferred design. Ideally, randomised placebo or
509
active comparator controlled trials (RCT) should be conducted for efficacy evaluation.
510
There are ethical concerns about the use of placebo when safe and effective alternative treatment is
511
available. Two-arm non-inferiority studies without a placebo-arm could be acceptable provided that the
512
selected comparator can be justified on the basis of a well-established efficacy, and an appropriately
513
justified non-inferiority margin can be predefined. Such comparative studies must have assay
514
sensitivity (see Guideline on the choice of the non-inferiority margin, EMEA/CPMP/EWP/2158/99).
515
In case the use of a placebo control group is considered necessary all efforts need to be made to
516
assure that the patient is not exposed to more than minimal risk. For example, randomisation can be
517
set with unequal allocation with fewer patients in the placebo arm, especially in case where there is a
518
control active treatment arm in the trial. Patients in the placebo arm are not left untreated, as
519
standard of care medication will be available to all patients recruited in the trial.
520
It is acknowledged that there is a limited pool of patients available for clinical trials in UC and
521
combined trial designs for induction and maintenance of remission can be accepted. Nevertheless the
522
design has to be adapted to allow interpretation of results in both phases and an element of dose-
523
comparison may be built into a maintenance phase considering that the dose may not be the same for
524
achieving as for maintaining remission.
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8.3.1.5. Safety in paediatric patients
526
Collection of safety data will always be required to identify any unexpected age-specific safety events.
527
For the confirmation of efficacy and to evaluate safety in larger populations long-term post-marketing
528
observational studies (i.e. registries) may be used.
529
Special attention should be paid to the fact that the spectrum of adverse reactions might differ in
530
children in comparison to adults. Therefore drug levels should be taken into account. Post-study/post-
531
authorisation long-term data, either while patients are on chronic therapy or during the post-therapy
532
period, are necessary to determine possible effects on maturation and development.
533
If there are concerns on the medicine’s impact on the immune system that cannot be addressed in the
534
pre-clinical development or by studies in adults but can be answered by clinical studies in children
535
(development of immune system, response to vaccination, etc.), appropriate studies or sub-studies
536
should be conducted. This is particularly true for a drug with new mechanism of action to be tested in
537
younger children (e.g. less than 6 years old) where adequate measures to evaluate the potential
538
impact of the experimental therapy on vaccination should be implemented.
539
The long-term evaluation of safety requires collection of data from larger number of patients for a
540
longer period of time, potentially into adulthood. Long-term safety could be studied in open label
541
extension studies and in post-marketing observational registry-type studies. The protocols for such
542
studies should define and record the risks of the medicinal product. The registry should preferably be
543
an established disease-based (rather than product-based) clinical registry and allow collection of long-
544
term data from a sufficient number of patients treated with different medicinal products.
545
8.3.2. Patients with acute severe colitis
546
Patients with acute severe colitis form an important subgroup of patients with UC. The definition of
547
acute severe colitis, which has most commonly been used, is that of Truelove &Witts. Limited amount
548
of data for this group of patients may be acceptable for this indication, but will need to be supported
549
by other data, (in particular safety data, but also data on efficacy in other subgroups of UC). Acute
550
severe colitis, refractory to corticosteroids, may be defined using indices that predict colectomy in this
551
population, e.g., the Swedish fulminant colitis index or the Oxford index. Evaluations should initially be
552
on a daily basis. Studies should be either active controlled (standard care including high dose
553
corticosteroids) or placebo-controlled add-on to standard care. Avoidance of colectomy short- and
554
long-term are relevant primary endpoints in this population.
555
8.3.3. Patients with pouchitis
556
Patients with pouchitis post-colectomy with ileal pouch-anal anastomosis form an important subgroup
557
of patients with UC. Design should be double blind, randomised and controlled. The management of
558
pouchitis aims at reducing bacterial overgrowth and inflammation but resistance to medical therapy is
559
reported in up to 20%. Antibiotics form the mainstay of treatment and can be used as control in
560
studies with new medicinal products in pouchitis. For acute pouchitis (< 4 weeks), metronidazole or
561
ciprofloxacin should be used as comparators. In chronic, antibiotic resistant pouchitis, placebo control
562
is acceptable. The diagnosis should be confirmed by typical clinical presentation, endoscopy and
563
histology. Efficacy in terms of symptoms as well as MH (including histological assessment) (co-primary
564
endpoints) should be demonstrated. The 18-point Pouchitis Disease Activity Index (PDAI), combining
565
all three aspects (symptoms, macro- and microscopic appearance of mucosa) has been used to
566
measure disease activity and response. However, this instrument is not fully validated and there are no
567
generally accepted definitions of response and remission. Nevertheless, the use of PDAI may be
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acceptable provided that response and remission are convincingly defined and provided that clinically
569
relevant effects in each of the main components of the score (symptoms as well as macro- and
570
microscopic appearance of mucosa) are demonstrated.
571
8.3.4. Patients with extra-intestinal manifestations
572
Extra-intestinal manifestations occur in a subgroup of patients with UC. They can be classified into
573
“reactive” symptoms associated with active colitis and manifestations that occur independently of the
574
inflammation (e.g. ankylosing spondylitis, pyoderma gangrenosum and primary sclerosing cholangitis).
575
Separate studies are not needed in this subgroup but response to treatment should be monitored in
576
trials and analysed separately. Primary sclerosing cholangitis is a pre-malignant condition and special
577
consideration should be given to this patient population when included in trials with new
578
immunomodulating agents.
579
9. Risk management plan
580
Post-marketing, a risk management plan (please see Guideline on Risk Management Systems for
581
Medicinal Products for Human Use) will normally have to be implemented in order to monitor possible
582
long-term consequences of use of immunosuppressive and/or immunomodulating drugs, including new
583
biologicals. Particular attention should be paid to infectious and/or malignant complications.
584
Furthermore, adverse reactions in different sub-population should be monitored. Whether new
585
treatments result in reduction in surgical intervention long-term is also of interest.
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