3.  NOTIFICATION   OF    AMENDMENTS   AND    RELATED MEASURES

3.1.  Legal basis and scope

105.  Article  10(a)  of Directive 2001/20/EC reads as follows:

‘After the commencement of the clinical trial, the sponsor may   make    amendments   to   the   protocol.   If   those amendments  are  substantial  and  are  likely  to  have  an impact  on  the  safety  of  the  trial  subjects  or  to  change the interpretation of the scientific documents in support of  the  conduct  of  the   trial,  or  if  they   are  otherwise significant,   the    sponsor   shall   notify   the    competent authorities   of   the   Member   State   or   Member   States concerned  of  the  reasons  for,  and  content  of,  these amendments  and  shall  inform  the  ethics  committee  or committees   concerned   in   accordance   with   Articles   6 (Ethics  Committee)  and   9  (Commencement  of  clinical trial).’

106.  In   view    of   the   identical   legal    consequences   of   an  amendment  that  is  ‘substantial  and  likely  to  have  an  impact  on  the  safety  of  the  trial  subjects  or  to  change  the interpretation of the scientific documents in support  of the  conduct  of  the  trial’  and  an  amendment  that  is  ‘otherwise  significant’,  the  term  ‘substantial  amendment’ used in this guidance refers to both types of amendments.

107.  Notification/submission  of  information (1)   is  only  obli- gatory  if  the   amendment  is  a  substantial  amendment. Directive  2001/20/EC  does  not  require  notification,  nor immediate  submission  of information  of non-substantial amendments.  Neither  national  competent  authorities  of the  Member  State  concerned,  nor  its  Ethics  Committee can   oblige   the   sponsor   to   submit   non-substantial amendments. In this regard, the rules for non-substantial amendments (cf. Section  3.6) apply.

3.2.  The notion of ‘amendment’

108.  The following changes do not count as an ‘amendment’ as

referred to in Article  10(a) of Directive 2001/20/EC:

—  a   change  to  the  documentation  submitted  to  the national   competent   authority   during   the   ongoing assessment  of  the  request  for   authorisation  by  the national  competent  authority   (for  these  aspects  see Section 2.1.4.2), and

—  a   change  to  the  documentation  submitted  to  the Ethics  Committee  during  the  ongoing  assessment  of the request for authorisation by the Ethics Committee.

109.  Article   10(a)   of   Directive   2001/20/EC   refers   only  to amendments  to  the  approved  protocol.  This  is  to  be understood     as     encompassing     all     documentation submitted in the context of the approved protocol.

110.  The   annual   safety   report    (ASR)   in   accordance   with Article  17(2)  of  Directive  2001/20/EC  is  not  per  se  an amendment  and thus does not have to be notified as a substantial    amendment    to    the    national    competent authority  of the  Member  State  concerned.  However,  the sponsor has to verify whether the data presented in the ASR  requires  a  change  to  the  documentation  submitted with the request for authorisation of a clinical trial. If this amendment  is  substantial,  the  rules  for  notification   of substantial amendments apply to these changes.

111.  A change of the contact person or in the contact details of the  contact person  (e.g.  a  change  of e-mail  or  postal address)  is  not   considered   as   an   amendment,   if  the sponsor    and    legal    representative    remain    identical. However,  the  sponsor  should  ensure  that  the  national competent  authority  of  the  Member  State  concerned  is aware  of  this  change  as  soon  as  possible,  in  order  to allow  the  national   competent  authority  to   exercise  its supervisory function.

3.3.  The notion of ‘substantial’

112.  Amendments  to  the  trial  are  regarded  as  ‘substantial’ where they are likely to have a significant impact on: the safety or physical or mental integrity of the clinical trial participants, or the scientific value of the trial.

113.  In  all  cases,  an  amendment  is  only  to  be  regarded  as ‘substantial’ when  one  or  both  of the  above  criteria  are met.

114.  It is up to the sponsor to assess whether an amendment is to  be  regarded  as  ‘substantial’.  This  assessment  is  to  be made on a case-by-case basis in view of the above criteria. While the responsibility for this assessment lies with the sponsor, in cases where the sponsor consults the national competent authority advice should be given without delay and free of charge.

115.  In applying these criteria, however, care has to betaken to avoid  over-reporting.  In  particular,  not  every  change  to the  clinical  trial  application  form  is  by  default  to  be considered as a ‘substantial’ amendment.

116.  The annual update of the IB in accordance with Article  8 of  Directive   2005/28/EC   is   not  per  se   a   substantial amendment. However, the sponsor has to verify whether the update relates to changes which are to be considered as  substantial.  In  that  case,  the  rules  for  notification  of substantial amendments apply to the change.

117.  The sponsor should assess also whether the combination of substantial amendments lead to changes of the clinical trial  to  an  extent  that  it  has  to  be  considered  as  a completely   new   clinical   trial,   which   would   then   be subject to a new authorisation procedure.

3.4.  Examples

118.  In  view  of  these  criteria  the  following  examples  should serve  as  guidance   for  the   case-by-case  decision  of  the sponsor.   These   examples   relate   only   to   the   aspects assessed  by  the  national  competent  authority  of  the Member  State  concerned.  For  aspects  considered  by  the Ethics  Committee, reference is made to the  Commission guidance based on Article 8 of Directive 2001/20/EC.

119.  With  regard  to  the  protocol,  the   following  is  a  non- exhaustive    list    of    amendments    that    are    typically ‘substantial’: (a)  change  of main objective of the clinical trial; (b)  change  of  primary  or  secondary  endpoint  which  is likely to  have  a  significant  impact  on  the  safety  or scientific value of the clinical trial; (c)  use of a new measurement for the primary endpoint; (d)  new  toxicological  or  pharmacological  data  or  new interpretation   of  toxicological   or   pharmacological data  which  is  likely  to  impact  on  the  risk/benefit assessment; (e)  a change in the definition of the end of the trial, even if the trial has in practice already ended;  (f)  addition  of a trial arm or placebo group; (g)  change  of  inclusion   or   exclusion  criteria,  such  as changes to  age  range,  if these  changes  are  likely to have  a  significant  impact  on  the  safety  or  scientific value of the clinical trial; (h)  reducing the number of monitoring visits; (i)  change   of   a    diagnostic   or   medical   monitoring procedure   which   is   likely   to   have   a   significant impact   on   the   safety   or   scientific   value   of   the clinical trial; (j)  withdrawal of an independent data monitoring board; (k)  change of IMPs; (l)  change  of dosing  of IMPs; (m)  change of mode  of administration of IMPs; (n)  a  change  of  study  design  which  is  likely  to  have  a significant  impact  on  primary  or  major  secondary statistical analysis or the risk/benefit assessment.

IMPs is short for Investigational Medicinal Products

120.  With  regard  to  the  protocol,  the   following  is  a  non- exhaustive  list  of  amendments  that  are  typically  not ‘substantial’: (a)  changes to the identification of the trial (e.g. change of title, etc.); (b)  the addition/deletion of exploratory/tertiary endpoints; (c)  a minor increase in the duration of the trial  (< 10 % of the overall time of the trial); (d)  an  increase in duration of > 10 % of the overall time of the trial, provided that: the  exposure  to  treatment  with  the  IMP  is  not extended;  the definition of the end of the trial is unchanged, and monitoring arrangements are unchanged; (e)  a  change  in  the  number  of  clinical  trial  participants per trial site, if the total number of participants in the Member  State  concerned  is  identical  or the increase/ decrease   is   insignificant   in   view   of   the   absolute number of participants; (f)   a change in the number of clinical trial participants in the Member  State  concerned,  if the total  number  of participants  is  identical  or  the  increase/decrease  is insignificant   in   view   of   the   absolute   number   of participants; (g)  a  change  in the  documentation used by the research team for recording study data (e.g. case report form or data collection form); (h)  additional  safety monitoring which is not part of an urgent safety measure but is taken on a precautionary basis; (i)   minor  clarifications to the protocol; (j)   correction  of typographical errors.

3.4.2.  Amendments  as regards the  IMPD

121.  With   regard   to    changes   in   the    IMPD,   guidance    is contained   in   Chapter   8   of   the    Guideline   on   the requirements to the chemical and pharmaceutical quality documentation    concerning    investigational    medicinal products in clinical trials (1).

3.4.3.  Amendments  as regards the  IB

122.  With regard to the IB, the following is a non-exhaustive list of amendments that are typically ‘substantial’: (a)  new   toxicological  or  pharmacological  data  or  new interpretation   of   toxicological   or   pharmacological data of relevance for the investigator; (b)  changes  to  the  reference  safety  information  for  the annual safety report.

3.4.4.  Amendments    as     regards    other     initial    documents supporting  the  request for  authorisation of the  clinical trial

123.  With regard to other initial documents, the following is a non-exhaustive  list   of  amendments   that   are   typically ‘substantial’: (a)  a    change    of    sponsor    or    the    sponsor’s    legal representative; (b)  the  revocation  or  suspension  of the  IMP’s  marketing authorisation.

 124.  With regard to other initial documents, the following is a list of amendments that are typically not ‘substantial’: (a)  any  change of persons other than the sponsor or his legal  representative,  for  example  applicant,  clinical research  associates  (CRAs)  who  monitor  the  clinical trial for the investigator, and  clinical research organ- isations  (CROs)  (note  that  the  responsibility  vis-à-vis the national competent authority for the clinical trial is always with the sponsor or his legal representative); (b)  any  change in the contact details of persons referred to in the documentation (see, however, Section 3.2 as regards contact details of the contact person); (c)  changes to the internal organisation of the sponsor or of  the  persons  to  whom   certain  tasks  have  been delegated; (d)  changes  in  the  logistical  arrangements  for  storing/ transporting samples; (e)  change of technical equipment; (f)   addition  or  deletion per se  of another Member  State or third country concerned.

3.5.  Who should be notified?

125.  Substantial    amendments   may   relate   to   information relevant   for    assessment   by    the   national   competent authority, the Ethics Committee, or both.

126.  For   substantial    amendments   to    information   that    is assessed  only  by  the  national  competent  authority  of the  Member  State  concerned,  the  sponsor  should  only notify   the   amendment   to   the   national   competent authority.

127.  For   substantial    amendments   to    information   that    is assessed,  according  to  Directive  2001/20/EC,  only  by the  Ethics  Committee  of  the  Member   State  concerned, the  sponsor  should  only  notify  the  amendment  to  the Ethics  Committee.  This  is  in  particular  of  relevance  for the information relating to:

—  the   clinical   trial    site   (Article    6(3)(f)   of   Directive 2001/20/EC),

—  the written information to be given to the clinical trial participant   in   order   to   obtain   informed   consent (Article  6(3)(g) of Directive 2001/20/EC), and2001/20/EC).

128.  These  aspects  are  addressed in the  separate  Commission guidance based on Article 8 of Directive 2001/20/EC.

129.  In   the    case    of   substantial   amendments   that   affect information  assessed  by  both  the  national  competent authority  and   the   Ethics   Committee   of   the   Member State    concerned,    the    sponsor    should    submit    the notifications in parallel.

130.  There   is   no    need   to   notify   ‘for   information    only’ substantial     amendments     to     one     body      (national  competent   authority   or   Ethics   Committee),   if   this  information is assessed by the respective other body.

131.  In  practice,  it  is  necessary  that  the  national  competent authority and the Ethics Committee in the Member State concerned  communicate  with  each  other  in  order  to ensure  the   exchange  of  expertise  or  information.  This may be in particular relevant, for example, for:

—  assessing    scientific    information    requiring    specific expertise,

—  ensuring  effective  inspections   of  clinical  trials   sites, and

—  updating relevant information in EudraCT.

3.6.  Non-substantial amendments

132.  The  sponsor  does  not  have  to  notify  non-substantial amendments to the national competent authority or the Ethics Committee. However, non-substantial amendments should be recorded and contained in the documentation when  it  is  subsequently  submitted,  for  example  in  the subsequent notification of a substantial amendment. This is of particular relevance for the Clinical Trial Application Form: This form should be updated in its entirety at the occasion of a substantial amendment. Documentation of non-substantial amendments should also be available on request  for  inspection  at  the  trial  site   or  the  sponsor premises as appropriate.

3.7.  Format and content of notification

133.  The   notification   of   a   substantial   amendment   should include the following:

(a)  a signed cover letter, including:

—  in  its  subject  line  the  EudraCT  number  and  the sponsor  protocol  number   (if  available)  with  the title  of  the  trial   and  the   sponsor’s  amendment code  number  allowing  unique  identification  of the substantial amendment. Care should be takento use the code number consistently;

—  identification of the applicant;

—  identification    of    the     amendment     (sponsor’s substantial    amendment    code    number and date).   One   amendment   could   refer   to   several changes  in  the  protocol  or  scientific  supporting documents;

—  a   highlighted   indication   of   any   special   issues related  to  the  amendment  and  indication  where the relevant information or text is in the original application dossier;

—  identification of any information not contained in the  Amendment  Notification  Form  that  might impact on the risk to trial participants;

—  where applicable, a list of all affected clinical trials with EudraCT numbers and respective amendment code numbers (see above);

(b)  the   Amendment    Notification   Form,   as   amended, which  is   published  in  Volume   10   of  EudraLex

The   Rules    Governing   Medicinal    Products   in    the European      Union.  Only      this      Amendment Notification Form should be used;

(c)  a description of the amendment:

—  an extract from the amended documents showing previous  and  new  wording  in  track  changes,  as well as the extract only showing the new wording;

—  notwithstanding the previous point, if the changes are so widespread or far-reaching that they justify an  entire  new  version  of  the  document,  a  new version  of the  entire  document.  In  this  case,  an additional table should list the amendments to the documents.  In  this  list,  identical  changes  can be grouped.

The  new  version  should  be  identified  with  the  date and an updated version number.

(d)  supporting information including, where applicable:

—  summaries  of data,

—  an updated  overall risk/benefit assessment,

—  possible     consequences     for     subjects     already included in the trial,

—  possible  consequences  for  the  evaluation  of  the results;

(e)  if a substantial amendment involves changes to entries on the clinical trial application form, a revised copy of the XML file incorporating amended data. If the form is  not  submitted  via  a  telematics  system,  the  fields affected  by  the  substantial  amendment  should  be highlighted in the revised form (3).

134.  Where  a  substantial  amendment  affects  more  than  one clinical trial of the same sponsor and the same IMP, the sponsor  may  make  a  single  notification  to  the  national competent  authority/Ethics  Committee  of  the   Member State  concerned.  The  cover  letter  and  the  notification should  contain  a  list  of  all  clinical  trials  affected  with their  EudraCT  numbers  and  respective  amendment  code numbers. If the substantial amendment involves changes to several clinical trial application forms, all forms should be updated (see Section  3.7).

3.8.  Time for response, implementation

135.  Article  10(a), second and third subparagraph, of Directive 2001/20/EC reads as follows:

‘On the basis of the details referred to in Article  6(3) and in accordance with Article  7, the  Ethics Committee shall give an opinion within a maximum of 35 days of the date of receipt of the proposed amendment in good and due form. If this opinion is unfavourable, the sponsor may not implement the amendment to the protocol.

If the opinion of the Ethics Committee is favourable and the  competent  authorities  of  the  Member   States  have raised   no   grounds   for   non-acceptance   of   the    … substantial  amendments,  the  sponsor  shall  proceed  to conduct    the    clinical    trial    following    the    amended protocol. Should this not be the  case, the sponsor shall either take account of the grounds for non-acceptance and adapt    the    proposed    amendment    to    the    protocol accordingly or withdraw the proposed amendment.’

136.  Accordingly, the Ethics Committee has to give within  35 calendar  days   an  opinion  on  a  valid  submission  of  a proposed substantial amendment.  If a  submission is not considered  as  valid  by  the  Ethics  Committee,  the  Ethics Committee should inform the applicant of this within the first  10 calendar days of this  35-day period. The reasons should be given.

137.  With  regard  to  the  national  competent  authority,  no deadline is set in Directive  2001/20/EC.,  and in view of the  approval  time  for  requests  for  authorisation,  the national   competent   authority   are   invited   to   respond within 35 calendar days of receipt of the valid notification of   an   amendment.   Validation    of   the   submission   is included in this period. If a submission is not valid  (for example, the dossier does not contain the documentation required   according   to   this   guidance),   the   national competent  authority are  invited to  inform  the  applicant of this within the  first  10  calendar  days  of this  35-day period. The reasons should be given. This response time may be extended if such extension is justified in view of the nature of the substantial amendment, for example if the national competent authority has to consult an expert group   or   committee.   In   such   cases,   the   national competent  authority  should  notify  the   sponsor  of  the duration of the extension and its reasons. If the national competent  authority states that  it  raises no grounds  for non-acceptance, the sponsor can implement the changes, even if fewer than 35 days have elapsed since the filing of the substantial amendment.

 138.  For amendments submitted to either the Ethics Committee alone  or to the  national  competent  authority alone, the sponsor may implement the amendment when the Ethics Committee   opinion   is   favourable   or   the   competent national   authority   has    raised   no   grounds    for   non- acceptance.

139.  Up until then, the trial can continue on the basis of the original documentation, unless the rules for urgent safety measures apply.

140.  Applicants  should  be   aware  that  these   procedures  are intended  to   ensure   rapid   and   efficient   processing   of substantial amendments. Against this background, unsatis- factory documentation is likely to lead to non-acceptance of the  substantial amendment. Non-acceptance  does  not prejudice the applicant’s right to resubmission.

141.  Upon approval, it is the sponsor’s responsibility to ensure communication of the changes to the investigators.

3.9.  Notification of urgent safety measures

142.  Article  10(b)  of  Directive  2001/20/EC  reads  as  follows:

‘Without prejudice to point (a), in the light of the circum- stances, notably the occurrence of any new event relating to  the  conduct  of  the  trial  or  the  development  of  the investigational medicinal product where the new event is likely to affect the safety of the subjects, the sponsor and the   investigator   shall   take    appropriate   urgent   safety measures  to  protect  the  subjects  against  any  immediate hazard.    The    sponsor    shall    forthwith    inform    the competent   authorities   of   those   new   events   and   the measures   taken    and    shall    ensure    that    the    Ethics Committee is notified at the same time.’

143.  Examples of urgent  safety measures are if, for reasons of safety of the clinical trial participants, a trial is temporarily halted   (see   Section    3.10)   or   additional   monitoring measures are set up.

144.  Urgent safety measures may be taken without prior notifi- cation to the national competent authority. However, the sponsor  must  inform  ex  post   the   national  competent authority  and   the   Ethics   Committee   of   the   Member State  concerned  of  the  new  events,  the  measures  taken and  the  plan  for  further  action  as  soon  as  possible. Where the initial contact is by telephone, this should be followed up, for reasons of traceability, by fax or e-mail. It should be followed by a written report.

145.  The  ex  post   notification  of  urgent   safety   measures  is independent of the obligation to:

—  notify substantial amendments  (see  above),

—  notify early termination of the trial within  15  days in accordance with Article 10(c) of Directive 2001/20/EC (see below, Section 4.2.2), and

—  notify adverse events and  serious adverse reactions in accordance  with  Articles   16   and   17   of   Directive 2001/20/EC.

3.10.  Temporary halt of a trial

146.  A temporary halt of a trial is a stoppage of the trial which is not envisaged in the approved protocol and where there is an intention to resume it.

147.  A temporary halt can be:

—  a substantial amendment, or

—  part  of  an  urgent  safety  measure  as  referred  to  in Article  10(b)  of  Directive  2001/20/EC.  In  this  case, the  notification   of  the  temporary  halt   of  a  trial should  be  made  immediately  and,  at  the  latest,  in accordance with the deadline set out in Article  10(c), second sentence, of Directive 2001/20/EC, within  15 days from when the trial is temporarily halted.

148.  The reasons and scope, e.g. stopping recruitment or inter- rupting treatment of subjects already included, should be clearly explained in the notification (in case of substantial amendment, see Section 3.7) or in the ex post information (in case of urgent safety measures, see Section  3.9).

149.  The restart of the trial should be treated as a substantial amendment providing evidence that it is safe to restart the trial.

150.  If the sponsor decides not to recommence a temporarily halted  trial  he  should  notify  the  national  competent authority  of  the   Member  States  concerned  within   15 days  of  his  decision  in  accordance  with  Article   10(c), second     sentence,     of     Directive      2001/20/EC     (see Section 4.2).

3.11.  Suspension/prohibition of a  clinical trial by the national competent authority in case of doubts about safety or scientific validity

151.  Article  12(1)  of  Directive  2001/20/EC  reads  as  follows:

‘Where   a    Member   State    has   objective    grounds   for considering   that   the    conditions   in    the   request    for

authorisation referred to in Article 9(2) are no longer met or  has  information  raising  doubts  about  the  safety  or scientific validity  of the  clinical  trial,  it  may  suspend  or prohibit  the  clinical  trial  and  shall  notify  the  sponsor thereof.

Before  the  Member  State  reaches  its  decision  it  shall, except  where  there  is  imminent  risk,  ask  the  sponsor and/or the investigator for their opinion, to be delivered within one week.

In  this  case,  the  competent  authority  concerned  shall forthwith  inform  the  other  competent  authorities,  the Ethics   Committee   concerned,   the   Agency   and   the Commission  of  its  decision  to  suspend  or  prohibit  the trial and of the reasons for the decision.’

152.  If the trial is terminated following a suspension, the rules on end of trial notification apply (see below, Section 4.2).

3.12.  Non-compliance  with  the  applicable  rules   on clinical trials

153.  Article  12(2)  of  Directive  2001/20/EC  reads  as  follows:

‘Where a competent authority has  objective grounds for considering  that  the  sponsor  or  the  investigator  or  any other  person   involved  in  the   conduct  of  the  trial  no longer    meets    the    obligations    laid    down,    it    shall forthwith  inform  him  thereof,  indicating  the  course  of action  which  he  must  take  to  remedy  this  state  of affairs.    The     competent     authority    concerned    shall forthwith   inform   the   Ethics   Committee,   the   other competent   authorities    and   the    Commission   of   this course of action.’

154.  The ‘course of action’ of the national competent authority should have a timetable for its implementation and a date when  the  sponsor  should  report  back  to  the  national competent authority on the progress and completion of its implementation.

155.  The sponsor should ensure that the ‘course of action’ set by the national competent authority is immediately imple- mented and report to the national competent authority of the  Member  State  concerned  on  the  progress  in  and completion  of  its   implementation   in  accordance  with the timetable set.

156.  The national competent authority must inform the other national  competent  authorities, the  Ethics  Committee  of the Member State concerned and the Commission of the ‘course of action’.