BIAN Lei, YANG Yue

(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

The Safety Monitoring System for Drug Clinical Trials

BIAN Lei, YANG Yue

(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

Objective To provide an important theoretical guidance and a practical base for standardizing timely and effectively the safety monitoring system of drug clinical trials by learning experiences from foreign mature practices under the trend of globalization for drug clinical research. Methods Framework of foreign drug safety monitoring system was systematically expounded by analyzing the safety reports, assessment reviews and risk control regulations in clinical trials in the ICH, the United States and the EU. Results and Conclusion At present, drug clinical safety monitoring system in China is still at initial stage, yet it can be perfected constantly by learning experiences from foreign countries to guarantee people’s safety in drug use.

drug clinical trial; safety report; monitoring system

Drug clinical research becomes the most important step in drug development, not only because it is crucial to final marketing approval, but also it is a process which swallows up most of the expense on drug development. Some statistics show that[1], clinical research expense accounts for nearly two-thirds of all the costs. In recent years, with the increasing costs and extending the cycle of development, more and more multinational pharmaceutical companies have moved their clinical trial center to China, India and other developing countries so that they can reduce the cost, speed up the clinical trials and benefit more patients.

1 Trend of the globalized drug clinical trial

ClinicalTrials.gov website was created as a result of the Food and Drug Administration Modernization Act of 1997 (FDAMA) which required to establish a registry of clinical trials information for both federally and privately funded trials conducted under investigational new drug (IND) applications to test the effectiveness of experimental drugs for serious or life-threatening diseases or conditions. The registration requirements were expanded after Congress passed the FDA Amendments Act of 2007 (FDAAA) which required more types of trials be registered and additional trial registration information be submitted. This led to the development of ClinicalTrials.gov and it became the largest and most professional database for clinical trial registration. Figure1 shows that the total number of studies has been registered on ClinicalTrials.gov since the registration date in 2000. By the end of June 23, 2014, 159251 clinical studies had been registered on this database. The number of registration is on the rise, especially when the International Committee of Medical Journal Editors (ICMJE) began requiring trial registration as a condition of publication under the uniform requirements in 2005, and also the registration requirements of FDAAA were implemented in 2007.

2 Increasing concern about the safety of clinical trials

As the number of clinical trials increases rapidly, people show great concern about the safety of clinical trials. So we should pay more attention to its safety when we are concerned about the clinical trial effectiveness. An analysis of termination reason for a new drug development before pre-market approval shows that[2]the safety factors account for 39.6%, among them 20.2% are for clinical safety and 19.4% are for toxicology. The unacceptable effectiveness factor for terminating the development accounts for 22.5%, and the rest are for investment consideration. They are shown in Figure 2.

Figure 1 Total registration number from the year of 2001 to 2013 in ClinicalTrials.gov

Figure 2 Reason for terminating the development of investigation drug

3 Safety monitoring system for clinical trials in western countries

Clinical trials in western countries have been developed for many years and their regulations and guidelines of drug safety monitoring and control are mature and good. Among them, the EU, United States and ICH are the good examples.

In the total 46 normative documents issued by ICH, 21 pertaining to the content of drug safety or adverse reaction have formed a relatively complete system of drug safety monitoring for clinical trials. The following table lists typical clinical guidelines for safety monitoring. These contain the content of safety data collection, evaluation, safety monitor measures, risk-benefit evaluation and so on. They clarify the specifications and requirements of safety in each period of drug development which form the base of clinical trial safety monitoring system in western countries.

Table 1 Important guideline for drug safety monitoring issued by ICH

E2A guideline published in 1994 clarified the requirements for safety data management, standard of safety event report and review. This guidance standardized the timeline and formation of unexpected serious adverse drug reaction (SUSAR) reports occurring in clinical investigations for notifying regulatory agencies, the minimum report standard and the processing measure of SUSAR reports arising after the trial. E6 pointed out how to collect and analyze serious adverse events for investigators, sponsors and ethic committee. E2B explained the requirements for safety data coding, terminology and vocabulary, data elements transfer and data source in clinical trial by using MedDRA.E2C, E2D and E2E made provision for the contents, forms and measures of risk evaluation and pharmacovigilance. The EU and FDA adopted these guidelines based on their actual situation.

In addition, the EU issued “the suspected serious adverse events database guide” (pharmacovigilance- clinical trials module) in April 2004. This guideline provided an important reference for clinical safety data entry control, communication methods and steps[3]. Another guidance named “detailed guidance on the collection, verification and presentation of adverse reaction reports from clinical trials on medicinal products for human use” made provision for the collection, verification, presentation and encoding the procedures of adverse event/reaction reports from clinical trials on medicinal products for human use and the responsibilities of the concerned parties[4]. In the same year, it also issued “Strategies to identify and mitigate risks for first-in- human clinical trials” which introduced the way to control the risk of first-in-human clinical trials by nonclinical and clinical evaluation[5].

FDA issued “Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs —Improving Human Subject Protection” in 2009, which made clear the responsibility of adverse events in clinical trials for sponsors and IRBs[6]. Meanwhile, FDA started to amend its regulations on application for new human drug and biological products trials (IND). FDA would codify timely review, evaluation, submission of relevant and useful information, international definitions and reporting standards into law. The revisions would improve the use of safety reports, reduce the number of reports that can not contribute to the safe development of drugs and expedite FDA’s review of critical safety information as well as to promote a consistent approach to safety reporting internationally. In December 2012, FDA issued two drug clinical research safety guidelines: “Guidance for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies”[7]and a special edition for small businesses[8].

Therefore, ICH, the EU and FDA provide the detailed instructions for data collection, evaluation, review and control and their safety monitoring systems for clinical research are clear and good.

4 Safety monitoring system for clinical trials in China

By contrast, the level of safety monitoring for drug clinical trials in China is still low. The Law on Pharmaceutical Administration and Regulations, the Drug Registration Regulations, the Good Practice of Clinical Trials and the Provisions of Drug Clinical Research all has requirements for drug clinical trials. Among them the Provisions of Drug Clinical Research made the demands for the safety monitoring and it requested that the serious adverse events of drug clinical trials should be reported to the Department of Drug Registration and the Department of Safety Supervision respectively within the timeline according to the requirement of the GCP. If the new adverse drug reaction or SAE occurs in the IV period of clinical trial, it also needs to be submitted to the National Adverse Drug Reaction Monitoring Center by using the SAE report form. The Drug Registration and Management Regulations request the timeline for SAE report is 24 hours. However, there are no clear rules on whether the content submitted meets the requirements of analysis or when to submit the follow-up report and what content should be submitted. Therefore, we can not get the analysis and evaluation after a report submitted. In recent years, China is gradually learning the advanced experience from Europe and the United States on clinical trials and safety monitoring system and has improved its monitoring level. In October 2013, CFDA issued the guidelines for vaccine clinical trials quality management (trial), which clearly regulated the reporting time limit of serious adverse event caused by vaccine should be 7 to 15 days, and the annual report is needed. This shows the trend that China is learning from the advanced countries. But at present, China does not have a regulation on the adverse event and safety evaluation of drug clinical trials. The lack of an effective guidance for safety monitoring in the process of drug clinical trials leads to the failure of drug clinical research safety data collection. Compared with the EU and the United States, China’s clinical drug safety monitoring system has not formed yet.

5 Conclusions

At present, China has not formed a safety monitoring system for drug clinical trials yet and we should have an effective monitoring in the process of clinical trials. While under the trend of globalized drug development, we should work hard to improve China’s safety monitoring system for drug clinical trials to be line with international standards and to establish an effective drug safety monitoring system. We must constantly improve the clinical safety monitoring system to guarantee peoples’ safety in medication.

[1] Supply Chain Management. The Innovation of Pharmaceutical Supply chain [EB/OL]. http://www.56885.net/news/200884/83170. html, 2008-08-04.

[2] YANG Huan. Pre-market Clinical Drug Safety Evaluation and Risk Assessment (4): Clinical Trial Management and Evaluation of Safety Data [EB/OL]. http://www.newstar-chem.com/display. asp?id=2432, 2009-03-16.

[3] European Commission. Detailed Guidance on the European Database of Unexpected Serious Adverse Reactions (Eudravigilance – Clinical Trial Module) [EB/OL]. http://ec.europa. eu/health/files/pharmacos/docs/doc2003/april/cp-guidanceeudravigilance_160403_en.pdf, 2004-04.

[4] European Commission. Detailed Guidance on the Collection, Werification and Presentation of Adverse Reaction Reports from Clinical Trials on Medicinal Products for Human use) [EB/OL]. http://ec.europa.eu/health/files/eudralex/vol-10/ 21_susar_rev2_2006_04_11_en.pdf, 2004-06.

[5] EMA. Strategies to Identify and Mitigate Risks for First-in-human Clinical Trials with Investigational Medicinal Products [EB/OL]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific guideline/2009/09/WC500002988.pdf, 2007-09-01.

[6] FDA. Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans [EB/OL]. http://www.gpo.gov/fdsys/pkg/ FR-2010-09-29/pdf, 2010-09.

[7] Guidance for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies [EB/OL]. http://www. fda.gov/downloads/drugs/guidancecomplianceregulatoryinformatio n/guidances/ucm227351.pdf, 2012-12.

[8] FDA. Guidance for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies- Small Entity Compliance Guide [EB/OL]. http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ucm332846. pdf, 2012-12.

Author’s information: YANG Yue, Professor, PHD. Major research area: Pharmaceutical affairs law & regulation and drug policy. Tel: 024-23986372, E-mail: yyue315@126.com