International sites must pay attention to detail

Audit readiness depends on it

[Editor’s note: In the second part of a two-part Q&A interview, Anatoly Gorkoun, MD, PhD, project manager of clinical operations of PSI Pharma Support International in Saint Petersburg, Russia, discusses how international sites and audits and regulatory factors.]

CTA: How should a site be prepared to maintain a trial audit capability, and what are some details on how these audits should take place?

Gorkoun: It is a good clinical practice (GCP) requirement to keep an audit trail. It’s covered at general GCP and/or study specific training sessions, such as a session on "Requirements re source documents maintenance." All international auditors mentioned that Russian sites maintain source documents very carefully. Normally, all sites maintain comprehensive patient charts, including the hospital chart or outpatient chart. All ancillary documents are enclosed in these charts, including lab reports, X-rays, ultrasound, computer tomography, position emission tomography, films, files, and descriptions, etc.

The sites are audited by internal quality assurance auditors, sponsors’ auditors, independent auditors, and Food and Drug Administration (FDA) auditors. The audit process in Russia doesn’t differ much from the audits done in the U.S. The only difference is that a translator is needed to assist auditors since the local source documents are written in the Russian language.

As part of GCP training, the investigators need to be taught about monitoring and audit. The investigators work with monitors on a regular basis, so the monitoring process is not an issue in most cases. Audits happen less frequently than monitoring visits, and the audit is an important event for each study. The investigators should be aware of it. So they need to be trained how to prepare the site for an audit. At the beginning of the study, the investigators should be provided with general knowledge about monitoring and the audit, but for in-depth preparations, it’s better to start doing it after the site receives audit notification.

When sites anticipate an audit, the best approach is to keep the site ready for the audit throughout the entire study.

There is no way to make corrections in the source documents before the audit, and there is no way to re-write any data. The auditors need to see a natural state of the site. When sites try to improve quality in a hurry, there is a very good chance they’ll make an even bigger mess or demonstrate noncompliance. We need to wait until the audit report is issued and then improve quality based on the audit report findings and recommendations.

Investigators need to understand the importance of accurately maintaining documents. Auditors say that if a monitor describes in monitoring reports a persistent absence of some documents at the site, such as screening logs and distribution of responsibilities list, and all of those documents appear in a nice order a day before the audit, then it might be reported as a finding. The auditors might state that the site does not maintain the documents throughout the study, putting together the on-site study file specifically for auditors before the audit. If the investigators think that it’s enough just to show documents during the audit, they are wrong. They need to realize that those documents must be maintained throughout the entire study, and it will be specifically checked by the auditors.

Keeping in mind the presentation on training issues for the SoCRA conference in Orlando, I had been asking auditors from different companies: "How do you see the preparation process? Do you have any specific message to deliver to investigators?"

What they said, and it was the same message with different wording, was, "Ask the investigators not to be scared by the audit. There is no need for specific preparations. Just ask the investigators to be available, to keep their facilities available, and to keep all source documents available. These are the best things they can do for us."

So, in preparing a site for an audit, it’s a good idea to instruct the investigators about the audit structure and the type of auditor’s activities. It’s a good idea for investigators to learn about any frequently asked questions, such as these:

  • What is the distribution of responsibilities at the site?
  • What is the process of patient identification?
  • What is the informed consent process?
  • How is the site’s work organized?

Investigators will need to think about these questions in order to provide the most complete responses.

Also, the investigators need to know how auditors evaluate quality, so it’s a good idea to explain to them the definitions of observations and the respective consequences (observations, major observations, critical observations).

CTA: What regulatory considerations in working with Russia are there, above and beyond what is already required in the United States?

Gorkoun: The Russian regulatory authority accepted the ICH GCP guidelines, and thus, it’s the main document, regulating clinical trial conduct in Russia.

CTA: Please describe how the monitoring process might differ for an international site?

Gorkoun: The monitoring process is regulated by Standard Operating Procedures (SOPs). I would not say that the monitoring process differs a lot in different countries. If the sites in different countries are involved in a global study, maximum uniformity will be applied to the monitoring process, and it’s the reason why the same monitoring procedures are applied for a global study in all countries. If several CROs are responsible for site management and monitoring in different countries, they will accept the same the same sponsor’s SOPs to provide uniformity of the monitoring process.

One difference can be noticed though—since in Russian and Eastern European countries most of the monitors are MDs, if there are any medical questions, these are discussed at the monitoring visit with an investigator by the monitor.

CTA: Is there anything else that American clinical trial sites need to know about working with Russian sites and other international clinical trial locations?

Gorkoun: Actually, American clinical trial sites, or Canadian or Australian, etc., don’t work directly with Russian sites. There are a lot of country-specific issues in each country, and, even if American or Australian sites know why enrollment is higher in Russia, it might be useless experience for other countries in some cases.

But knowledge of all those features can be helpful for American and other pharmaceutical companies who are running global clinical trials in Russia and Eastern Europe.

First of all, Russian sites are not overloaded with clinical trials, so there is a potential.

The Russian investigators believe that it’s prestigious to run global trials at their sites, and so some of the motivation factors are international involvement, experience, publications, and recognition.

An investigator’s grant is another of the motivation factors.

Among the important things to take into account is the medical insurance system, which is different in different countries. It’s obvious that if the patient has the most complete medical insurance it will lead to his/her reluctance to be involved in most clinical trials. If the patient expects more benefits from the trial due to availability of free sophisticated medical procedures/examinations and the best treatments, which are better than what can be provided by the patient’s basic medical insurance, then such a patient will agree to become a clinical trial subject more willingly.

In different countries, we can face different medical systems. They can be centralized, decentralized, private, or mixed. For instance, if we need to train the investigators in enrollment issues, it might be different for sites in countries with different systems. In some countries, especially those with a centralized medical system, it’s much easier to organize patient referral networks to enroll more patients, while for sites in other countries it might be a very difficult task to have patients referred to a clinical trial site. As for Russian sites, the establishment of referral networks is a routine practice and usually contributes to a high enrollment rate.