IFPMA Response to World Health Organization International Clinical Trials Registry Platform (ICTRP) Consultation 30 September 2005

Transcription

1 IFPMA Response to World Health Organization International Clinical Trials Registry Platform (ICTRP) Consultation 30 September 2005 Introduction In January 2005, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), the European Federation of Pharmaceutical Industries and Associations (EFPIA), the Japanese Pharmaceutical Manufacturers Association (JPMA), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the Canada s Research-Based Pharmaceutical Companies (Rx&D) issued a joint Position on the industry commitment to make information publicly available on on-going clinical trials and completed clinical trials. A complementary position was issued in September 2005 which clarifies issues related to disclosure of sensitive information via clinical trial registries. It reconfirms the understanding of the agreement reached at the WHO Technical Consultation Meeting on Clinical Trials Registration Standards held on April 2005 and explains the circumstances in which, if necessary, sponsors may wish to delay the release of information regarded as being sensitive. This information will be disclosed, at the latest, after the drug is first approved in any country for the indication being studied. On 21 September 2005, IFPMA launched its Clinical Trials Portal as a further commitment of the industry to transparency in the interest of patients and healthcare professionals (Portal URL is The Portal s search engine has been programmed to access relevant on-line sources of clinical trial information. These include individual pharmaceutical company sites, sites run by third parties working on behalf of these companies, pharmaceutical industry association resources, such as the US pharmaceutical industry association (PhRMA) site ( and government sites that routinely carry details of industry trials, such as the US National Library of Medicine s ( Additional sites will be added as they become available. IFPMA therefore welcomes the opportunity to provide comments on the WHO initiative, which should support its pragmatic implementation: WHO Registration Data Set Unique ID Assignment Register Certification

2 Key Points WHO Registration Data Set (see also detailed comments in the table) We note that the terminology used in the proposed WHO Registration Data Set differs from that agreed at the WHO April meeting. To avoid confusion and ensure consistency, we urge WHO to use the terminology agreed for the minimal data set at the World Health Organization (WHO) Technical Consultation on Clinical Trials Registration Standards Meeting (25-27 April 2005). This terminology is also used by the International Committee of Medical Journal Editors (ICMJE) 1. Detailing register content, the WHO states that "each register entry must contain at least the entire WHO Registration Data Set". As agreed to by the stakeholders at the WHO Technical Consultation on Clinical Trials Registration Standards Meeting (25-27 April 2005), five data items (#10, 13, 17, 19, 20) may be regarded as sensitive for competitive reasons by the sponsor who may wish to delay the release of the information. This needs to make it clear in the chart by highlighting the five fields that may have delayed disclosure (for example, items be clearly noted with an asterisk (*)) and by providing a detailed footnote. While we consider proposals to use controlled vocabularies for trial registration have merit, there are a number of practical issues to be overcome (e.g. what to do in case where there is no generic name for the investigational medicine or when a primary outcome is unprecedented). In addition agreement would be needed on the vocabulary to be used and this would need to be implemented in all primary registers in order to reach consistent language. Resolution of these issues is likely to require considerable time and resources and delay the WHO Platform. We suggest that WHO build the Platform using the minimal data set agreed at the WHO meeting in April and consider enhancements on an ongoing basis once the platform is up and running. A number of data elements include additional information to that agreed at the WHO meeting in April 2005, for example, contact information for funding sources and the inclusion of ethics committee ID numbers. It is of vital importance that the information essential to meeting the primary objectives of trial registration are included while not unnecessarily distracting trial sponsors and/or consuming additional resources. We consider the additional information unnecessary: it puts a large burden on pharmaceutical companies and in particular on sponsors from academia or collaborative groups and is of limited value to patients and physicians. 1 Is This Clinical Trial Fully Registered? A Statement From the International Committee of Medical Journal Editors JAMA, June 15, 2005 Vol 293, No. 23

3 Unique ID Assignment The flow chart which illustrates the process of assigning a WHO Clinical Trial Unique ID (WHO CT UID) is, without explanation, extremely difficult to follow and the process timing in its current form is hardly viable. Nonetheless, the need for a WHO CT UID has not been demonstrated and the proposed process will risk delay registration of trials and an additional number will cause considerable confusion. We believe that the number assigned by the primary register (e.g. clinicaltrials.gov) can adequately serve as the unique clinical trial number for registration purposes. We do not support the proposal for ethics committees/irbs to approve the WHO Registration Data set prior to submitting to a primary register. As an international requirement for all clinical trials involving humans, Sponsors and Principal Investigators submit protocol to ethics committees/irbs, for their approval. Requiring an ethics committee/irb to confirm registration is outside of their normal remit, and could place an additional burden on already overburdened ethics committees/irbs. This could lead to additional costs and occasional delay in approval and initiation of clinical trials, a result that would run counter to stakeholder interests. We would suggest that the sponsors of primary registers should have a mechanism in place to run occasional checks in the context of Quality Assurance procedures comparing the registry content with the trial protocol. We do not support proposals to register trials before ethics committee/irb approval because it does not aid patient enrollment or increase the ability to track the subsequent disclosure of clinical trial results. Sponsors have an obligation to devote resources to promptly complete the registration of clinical trials. However the resources required to continually update information on clinical trial registries because of alterations/changes agreed with ethics committees/irbs could be considerable. A requirement to register clinical trials prior to IRB approval (i.e., before their initiation) is likely to result in more changes to records than if registration took place at the start of patient enrollment. As mentioned in the commitment made by the research-based pharmaceutical industry in its Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases, issued in January 2005, the industry supports the requirement to register trials within 21 days of the initiation of patient enrolment. We do not support the requirement to place the unique identification number on informed consent documents. The benefit, to the patients and investigators utilizing the form, of including such a number on informed consent documents is not apparent. Moreover, this is not practical as the number will be assigned after the informed

4 consent documents have been reviewed by ethics committees/irbs and inclusion of such a number is likely to delay finalization of informed consent documents and recruitment of patients. Register Certification Reference is made to an escrow mechanism as the mechanism to delay certain data elements. However the WHO meeting in April did not agree such a mechanism and concluded that WHO will convene a group to develop a mechanism. This escrow mechanism should therefore be removed from the register certification requirements and it should be made clear that a mechanism is yet to be developed. WHO's Quality Assurance (QA) requirements as detailed in the Proposed Register Certification Criteria are far reaching, especially the points regarding checking funding sources, security and provisions against data corruption/loss and uptime. The explicit role of most clinical trial registries is to allow patients/providers to find relevant clinical trials in which to enroll. Verifying the above-mentioned points is an additional burden that is not warranted. We would suggest developing more pragmatic QA measures at a round table including WHO and IFPMA in order to assure that such measures are more viable. The WHO proposal mentions fees, application- and annual-, for certification as well as for issuance of CT-UID. Since we do not see significant benefits neither for companies nor for patients resulting from this initiative we would expect a more detailed rationale for the proposed charges as well as possible estimates of such fees.

5 . IFPMA Comments on WHO Registration Data Set Old Name (April 05) Unique trial number Trial registration date Item Definition/Explanation IFPMA Comments New Name Field Value Primary Register and Trial ID # Date of Registration in Primary Register Select Certified Register Trial ID # Secondary IDs Other Trial ID#s Issuing Authority Select name of Certified Register submitting the CT-UID request (the trial's "Primary Register"), and that register's registryspecific unique ID assigned to this trial. 1 Jan Date when initial WHO Registration Data Set was submitted to the Primary Register DD/MM/YYY. ID Number Click to add more Other identifying numbers and issuing authorities besides the Primary Register. Include at least the name and trial ID# from: the Research Ethics Board of the main study site, and all other certified and noncertified trial registries that have issued a number to this trial. Other ID numbers (e.g., sponsor name and number, funding agency and grant number) may also be submitted. There is no limit on the number of Other The need for a WHO CT-UID has not been demonstrated. The primary register ID number can be used for registration purposes and should be sufficient (for tracking purposes etc.). We support the ICMJE definition: "The unique trial number will be established be the primary registering entity (the registry)." We agree with the definition. This should be established by the Primary Register as described by ICMJE. The old name Secondary IDs should be retained. This is the term agreed at the WHO meeting in April and is the term used in the ICMJE criteria. Secondary IDs are meant to provide additional relevant information when available, such as protocol number or sponsor trial ID number. In some cases, there may be no relevant

6 Trial ID numbers that can be provided. secondary ID. The Research Ethics Board identification number should not be a required secondary ID: 1. The purpose of this number is for the Ethics Research Board to identify the trial in correspondence. 2. Not all Ethics Research Boards provide a unique trial ID number for each study. Some ethics committees identify the study by an abbreviated title only. 3. For trial registration/search purposes the Primary Register s unique ID number is sufficient. 4. For multicentre multinational trials there will be many Ethics Boards and Ethics Board ID numbers. Posting all this information is not necessary and may cause confusion. We believe that the trial ID assigned by the primary register is sufficient and therefore agree with the ICJME definition: May be assigned by sponsors or other interested parties (there may be none). Clinicaltrials.gov also notes that there may be none. 4. Funding source(s) Funding Source(s) Name Address or Contact Information Source(s) of monetary support for the trial (e.g., funding agency, foundation, company). It is not necessary to provide the address or contact information for funding sources. This information is not relevant to the objectives of trial registration and if needed could be

7 obtained from the research contact. Click to add more The ICMJE criteria do not include Address or Contact Information and should be deleted. 5. Primary sponsor Primary Sponsor Name Address or Contact Information The individual, organisation, group or other legal person taking on responsibility for securing the arrangements to initiate, manage and finance a study (including arrangements to ensure that the design of the study meets appropriate standards and to ensure appropriate conduct and reporting). The primary sponsor is normally the main applicant for regulatory authorisation to begin the study. It may or may not be the main funder. It is not necessary to provide the address or contact information for the primary sponsor. This information is not relevant to the objectives of trial registration and if necessary could be obtained from the research contact. The ICMJE criteria do not require Address or Contact Information. 6. Secondary sponsor(s) Secondary Sponsor(s) Name Address or Contact Information Click to add more Additional individual, organisation or other legal person that has agreed with the primary sponsor to take on responsibilities of sponsorship. A secondary sponsor may have agreed o o o to take on all the responsibilities of sponsorship jointly with the primary sponsor; or to form a group with the primary sponsor in which the responsibilities of sponsorship are allocated among the members of the group; or to act as the sponsor s legal representative in relation to some or all of the trial sites. The definition should include the term if any as there may not be any secondary sponsors. Language should clearly specify that the secondary sponsor may or may not have responsibility over the entries made for the study registration. It is not necessary to provide the address or contact information for the secondary sponsor. This information is not relevant to the objectives of trial registration and if necessary could be obtained from the research contact. The ICMJE criteria do not require Address or Contact Information.

8 7. Responsible contact person Contact Person address address of the person who will respond to queries from the public The old name responsible contact person should be retained. This is the term agreed at the WHO meeting in April and is the term used in the ICMJE criteria. We advocate for this field to allow for sponsors to provide an address OR telephone contact number. A name should not be required. Many sponsors currently have tollfree contact number established to answer questions from the public. Providing a central call center that can triage questions appropriately is much more efficient and personal than an address that would require constant updating for accuracy. 8. Research Contact Person Lead Principal Investigator Name Affiliation Name and affiliation of the person with legal and scientific responsibility for the trial. For a multi-center study, enter the lead Principal Investigator. The old name research contact person should be retained. This is the term agreed at the WHO meeting in April and is the term used in the ICMJE criteria. The research contact may either be the lead principal investigator or a person within the organization with the scientific knowledge/background to respond to scientific inquiries. We advocate for this field to allow for sponsors to provide an address or telephone contact number. In addition the name of the person should not be required.

9 When a customer calls this number or sends an and requests specific scientific/legal information about a particular study, the question will be triaged appropriately and the customer will be put in touch with the research contact person for that study. We agree with the ICMJE definition: Person to contact for scientific inquiries about the trial. 9. Title of the study 10. Official scientific title of the study Public Title Protocol title intended for the lay public. The old name title of the study should be retained. This is the term agreed at the WHO meeting in April and is the term used in the ICMJE criteria. Scientific Title Scientific title, including the intervention name, condition, and primary outcome. Example: "A Randomized Controlled Trial of Chocolate on Beck Depression Scores in Patients with Seasonal Affective Disorder" We agree with this definition. The definition should align with the ICMJE criteria which states that this can be omitted if the researchers wish. The old name official scientific title of the study should be retained. This is the term agreed at the WHO meeting in April and is the term used in the ICMJE criteria. Scientific titles should include the intervention name and condition. We do not see the necessity to the requirement to include the primary outcome of the study when this information is already shown in a different field. This may confuse the stakeholder.

10 We regard the ICMJE definition to be more pragmatic: This title must include the name of the intervention, the condition being studied, and the outcome (eg, The International Study of Digoxin and Death from Congestive Heart Failure). *The definition should make it clear that registration of this field may be delayed for competitive reasons as agreed at the WHO meeting in April. 11. Research ethics review Research Ethics Board Approval Yes Whether or not this trial has received final research ethics board approval at the time that the CT-UID was requested. The old name research ethics review should be retained. This is the term agreed at the WHO meeting in April and is the term used in the ICMJE criteria. To ensure trials are registered in a timely fashion, this definition should be Whether or not this trial has received at least one research ethics board approval. 12. Condition Disease or Condition Studied Controlled Term 1 Click to add more Primary disease(s) or condition(s) studied (e.g., depression, breast cancer). Select the appropriate controlled vocabulary term. We agree with the definition. However use of a controlled vocabulary term requires further detail as to the vocabulary to be used and the agreed use of these terms in all primary registers. This is not a requirement for ICMJE and was not agreed or discussed at the WHO meeting in April.

11 13. Intervention(s) Intervention(s) Intervention name Controlled Term 1 Duration, other details Click to add more interventions The specific name of the intervention(s) being studied, selecting the generic name where applicable (e.g., zidovudine, self'- hypnotic relaxation) from the controlled vocabulary. For multi-armed studies, the intervention(s) for each arm should be described. If an active control is used, be sure to enter in the name(s) as well. For each intervention, describe other intervention details (duration, mode of administration, etc) Intervention names should be provided. However the use of controlled vocabulary terms may not be practical since some investigational drugs may only have a compound number (no generic names). Using a vocabulary would unnecessarily delay registration of trials. In addition, a controlled vocabulary would require constant updating. We agree with the ICMJE definition and suggest this is used: A description of the study and comparison/control intervention(s) (for a drug or other product registered for public sale anywhere in the world, this is the generic name; for an unregistered drug the generic name or company serial number is acceptable). The duration of the intervention(s) must be specified. *The definition should make it clear that registration of this field may be delayed for competitive reasons as agreed at the WHO meeting in April. 14. Key inclusion and exclusion criteria Inclusion and Exclusion Criteria Eligibility criteria for participant selection, including age and gender criteria. Be sure to include all clinically relevant criteria. The old name key inclusion and exclusion criteria should be retained. This was agreed at the WHO meeting in April and is the term used by the ICJME. This enables important information to be registered while not providing the detail which is not relevant to meet

12 the objectives of trial registration. The patient should be able to determine eligibility for a certain study from a short, but comprehensive list containing all key patient characteristics Study type Anticipated trial start date Study type Date of First Enrollment Randomized? Controlled? Yes Yes A trial is "randomized" if participants are/were assigned to intervention groups by chance. A trial is not randomized if participants are/were expressly assigned to intervention groups. A trial is "controlled" if participants can/could have been assigned to receive a placebo, an active control, or a dose comparison, or a historical control will be/was used. 1 Jan Estimated date of enrollment of the first participant if trial has not yet started recruitment, or the actual date of first enrollment if the first participant has already been enrolled (DD/MM/YYYY). We agree with the definition. We agree with the definition. 17. Target sample size Target Sample Size Number of participants that this trial plans to or had planned to enroll. We agree with the definition. The definition should make it clear that registration of this field may be delayed for competitive reasons as agreed at the WHO meeting in April. 18. Recruitment status Recruitment Status at Time of CT-UID Request Not yet recruiting Recruitment status of this trial at the time that the CT-UID was requested. o Not yet recruiting: participants are not yet being recruited or enrolled o Recruiting: participants are currently being recruited and enrolled o No longer recruiting: participants are no longer being recruited or enrolled This definition should align with the ICMJE definition: Is this information available (yes/no) (if yes, link to information).

13 o Completed: participants are no longer being recruited; data analysis is complete o Suspended: recruiting or enrolling participants has halted but potentially will resume o Terminated: recruiting or enrolling participants has halted and will not resume 19. Primary outcome Primary Outcome(s) Outcome Name Controlled Term 1 Timepoints Click to add more Outcomes are specific measurements or observations used to measure the effect of experimental variables in a study. The Primary Outcomes are the specific measures that will be used to determine the effect of the intervention(s). Select the controlled vocabulary term for each and every primary outcome of the trial. Also provide all the timepoints at which each outcome is to be measured. Examples: Outcome Name: all cause mortality, Timepoints: one year; Outcome Name: score on a depression rating scale, Timepoint: 6,12, and 18 weeks The use of controlled terms could be problematic where the sponsor has developed a novel endpoint/outcome for the trial. This risks delaying registration of the trial. This is not a requirement for ICMJE and was not agreed or discussed at the WHO meeting in April. The definition should make it clear that registration of this field may be delayed for competitive reasons as agreed at the WHO meeting in April. 20. Key secondary outcomes Secondary Outcomes Outcome Name Controlled Term 1 Timepoints Click to add more Outcomes are specific measurements or observations used to measure the effect of experimental variables in a study. Secondary outcomes are measures other than the primary outcomes that will be used to evaluate the intervention(s), and that are specified in the study protocol. Select the controlled vocabulary term for each secondary outcome of the trial. Also provide all the timepoints at which each outcome is to be measured. Examples: Outcome Name: cardiovascular mortality, Timepoint: 6 months; Outcome Name: functional status, Timepoint: 4 and 8 weeks The old name key secondary outcomes- should be retained. This was agreed at the WHO meeting in April. Providing all secondary outcomes is not necessary to meet the objectives of trial registration and may only confuse prospective trial participants. Time points should not be required. For some trials this information will be overly complicated for primary and key secondary outcomes. Also note that the main protocol

14 register clinicaltrials.gov restricts the number of characters for this field. The definition should make it clear that registration of this field may be delayed for competitive reasons as agreed at the WHO meeting in April. If items are escrowed, the Primary Register must also submit to the ICTRP the anticipated date of last follow-up of any participant (for starting the clock on removal of items from escrow). We suggest removing the discussion of how the delayed disclosure mechanism will work. A committee has to be established by the WHO to fully operationalize the delayed disclosure mechanism. Therefore, requirements for this account are premature.