The Fundamentals of Clinical Research. P. Michael Dubinsky

5.3 Regulatory Affairs

      The regulatory affairs organizational group in a drug/pharmaceutical firm is always assigned as the primary point of contact for interactions with competent authorities. Therefore, a representative from the group should be part of the clinical development core team from the beginning of any clinical development initiative. Regulatory affairs will not be the only group or person that communicates with a regulatory or competent authority but they must be aware of all communications and in most situations will review the substance of communications for consistency with company and regulatory policy.

The functional responsibilities that are assigned to Regulatory Affairs include all marketing and development related applications for a pharmaceutical drug including amendments and supplements to those applications. Regulatory affairs will also be responsible for coordinating the assembly of data and information used to support the various applications. In the case of drug development applications such as an FDA Investigational New Drug (IND) Application regulatory affairs will likely be the conduit for all communications with the regulatory authority whether electronic (e.g. video conference/phone), written, or face‐to‐face. Having a central point of contact and it being a regulatory affairs group is an approach which is favored by the regulatory authorities. They prefer to have one central point of contact for communications. It is also in the best interests of a firm to have communications processed through a central coordination point. That way there is institutional knowledge and awareness of what is being communicated, how it fits with what has been previously communicated and an understanding of the impact, if any, that the information being transmitted will have on the program, project, or application involved. There may be times when the information is communicated by an organizational group other than regulatory affairs an example being pharmacovigilance/adverse experience reports. Even then the regulatory affairs group needs to be involved to ensure continuity and completeness.

      So how does that intersect with meeting GCP expectations?

      Basically, the regulatory affairs staff in a firm are charged with ensuring that the information and data reported on applications for pharmaceutical drug development is accurate, complete, original, and supported by facts. They are expected to sign off on all submissions to regulatory authorities and by doing so they guarantee the veracity and soundness of the information being submitted. In theory they could be held personally responsible for any inaccuracy, untruth, or omission found as part of a submission. Does that mean they double check all information? They might in some situations. The reality is that knowledgeable and seasoned regulatory affairs staff members have an in‐depth working knowledge of all the elements of the drug development processes and they practice a policy of accept and verify. They receive and/or request information from members of the drug development team to populate a submission but then perform verification on a portion of the data to be sure of accuracy and completeness. It is part of their training and job to know, understand, and be fluent in GCP as well as other GXP requirements.

5.4 Interacting with Regulatory/Competent Authorities

There are a number of mechanisms utilized to communicate with regulatory authorities and while none are unique to drug development it is useful to reflect on them and on the manner, in which they are arranged, documented and records maintained. As mentioned earlier communications will occur through one of three means – electronic means such as videoconferencing or telephone; face‐to‐face in a meeting or in a written submission. E‐mail would be considered as a written submission. The choice of which mechanism to use may take into consideration a number of factors. Factors such as the stage of development, the nature of the investigational product (IP), the circumstances prompting the need to communicate and the wishes of management can all be important forces when it comes to deciding which approach to choose. From the standpoint of GCP the sponsor is expected to establish and maintain the set of essential documents which represent the evidence that the trial was conducted in conformance with GCP and the applicable regulatory requirements. Records are kept by all the players in the clinical trial process, e.g. investigator, IRB, but the sponsor is responsible for the trial master file (TMF). The TMF is that central repository where the entire set of trial related documentation is maintained. Whether the records are hard copy or electronic the sponsor’s regulatory affairs unit is generally in charge of those records being organized and up to date if and when needed. If you refer to Chapter 29 Essential Documents – the TMF is discussed in detail. It is worth mentioning, and we will several times in the text that the documents which populate the TMF represent the evidence that the trial was conducted in compliance with GCP.

      Regulatory authorities have established ground rules for official communications and they live by those rules. For example the US FDA’s Center for Drug Evaluation and Review has procedures defining types of meetings they will arrange with sponsors in terms of timing, topic, pre‐meeting documentation, etc. [2] A trial sponsor should not expect to just send an E‐mail or make a telephone call to arrange a meeting. Regulatory authorities have just so many people resources and those resources have a range of responsibilities, so requests for meetings are controlled closely.

      Even with the complexities that accompany arranging a meeting they are an excellent framework for ensuring that the parties are on the same page about key aspects of the trial, such as the IP, the objectives, the entire nature, and scope of the endeavor. It is important for the sponsor to be certain their records of any meetings are as complete and clear as possible about any agreements, disagreements, and commitments made by the sponsor or the competent authority. Such factors play into the GCP arena in sometimes unexpected ways. For example if the sponsor makes commitments about the approach to monitoring, training or IP handling during meetings with the competent authority during a meeting prior to a Phase commencing and it is determined later that commitment was not kept it may prove very problematic. Such commitments actually become an element of GCP for the trial even if they are not specifically mentioned in the ICH E6(R2). It should be kept in perspective that GCP like the other GXP requirements are a baseline set of minimum requirements. Sponsors must meet the baseline requirements but the manner in which they implement them is usually left to the sponsor, IRB or site.

      Applications for permission to initiate a clinical trial, e.g. IND or CTA, along with their amendments and supplements also bind the sponsor and other trial players to aspects of GCP. Competent authorities as part of their codified rules take the time to describe the expectations that are in place for sponsors, investigators, IRBs, and in some ways even subjects. Sponsors commit in writing to ensure compliance with all applicable requirements. If those commitments are not honored there are severe penalties which may be imposed. So compliance with GCP must become a cultural force in the entire scheme of conducting a clinical trial.

5.5 Communicating with Regulatory/Competent Authorities and Others

      A good way to begin this portion of the discussion on communication is to recall ICH E6(R2) Principle 2.10 which reads: All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.

      Citing this principle makes sense here because recording, storing, and reporting on the large number of communications which will take place as part of the clinical trial scheme calls for training, a commitment to the record keeping fundamentals embodied in ALCOA [3] and a willingness on the part of staff to take the time to create a record. ICH E6(R2) does not use the terminology ALCOA but at section 4.9.0 states that source data should be attributable, legible, contemporaneous, original, accurate, and complete.

Earlier we noted the ways in which communication will occur with the regulatory authority. Meetings will generally involve a relatively small number of people and there will be a person appointed to act as the executive secretary or notetaker. During the course of a trial however there may be numerous times when a member(s) of the trial team will interact with a member(s) of the regulatory authority on a topic specific to their role on the trial team. It will be essential that those