According to international guidelines, the treating physician (investigator) is responsible for the medical
care of the individual trial subject (Declaration of Helsinki 3§ and ICH GCP 4.3). The coding system in
blinded trials should include a mechanism that permits rapid unblinding (ICH GCP 5.13.4). If the blinding
is prematurely broken, it is the responsibility of the investigator to promptly document and explain any
unblinding to the sponsor (ICH GCP 4.7).
The medical care of the trial subjects includes medical decisions such as whether to start or stop
treatment or institute alternative treatment if required. In emergency situations the treating physician,
often an investigator, may need to break the treatment code immediately, or as quickly as possible if
he/she finds it is in the best interest of the trial subject. Consequently, in order to do so, the investigator
must have unrestricted and immediate access to break the treatment code.
Some sponsors have recently introduced a code breaking system that requires the investigator to contact
a sponsor representative and only after discussion with the representative, the investigator receives
information that unblinds the treatment. Some sponsors have even added a requirement that the
investigator submits a written form after the phone call before receiving the information that unblinds the
treatment.
It is the opinion of the EMA GCP Inspectors Working Group (GCP IWG) and the Clinical Trial Facilitation
Group (CTFG) that the responsibility to break the treatment code in emergency situations resides solely
with the investigator. Consequently the sponsor can’t require or insist on being involved in the decision to
unblind, stall or delay in any way the unblinding of trial subject treatment in emergency situations. The
groups also strongly recommend that any sponsor who has introduced or is applying such a system
should immediately revise it in order to be compliant with international guidelines.
Breaking the treatment code is usually conducted via code envelopes or electronic systems such as
telephone or web based systems such as IVRS and IWRS. When using these kinds of systems the
investigator must have direct access in order to break the blind without the interference of the sponsor in
any way. In support of electronic systems, a backup system enabling unblinding of treatment must be
provided. The CTFG and the GCP IWG acknowledge that such backup systems are operated by the
sponsor in a manual way and that the investigator or other treating physician can contact the sponsor
staff to unblind the treatment. Still, the sponsor is not entitled to stall or reject unblinding.
Code breaking instructions should be specified clearly in the clinical trial protocol.
