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How Italy's new quality-driven regulations will ask more of CROs conducting activities in the country.
After several calm years, clinical trials in Italy are now experiencing a turbulent period. Not only has the number of new trials per year increased consistently, from approximately 500 in 2000 to almost 800 in 2007, the regulatory landscape has also changed a lot.1 The authorities have recently released new laws and regulations favoring strong harmonization and clarifying their intent.
Among the key actors in clinical research are Contract Research Organizations (CROs), which play a leading role. The typology of CROs in Italy is heterogeneous, ranging from very small companies—sometimes just more than a one man operation—to local branches of international companies.
In order to harmonize this diversified area, the Italian authorities released a new regulation aimed at defining the minimum quality standards for CROs operating in the country.
The document, published in November 2008 and titled "Definition of the Minimum Requirements which Contract Research Organizations (CROs) Shall Satisfy in order to Work within Clinical Trials on Medicinal Products,"2 represents a unique case in the landscape of international pharmaceutical regulations. These new rules are not only of interest to Italian CROs, they also apply to any foreign CROs operating in Italy. Therefore, international CROs performing activities like monitoring or auditing must comply with the requirements of the Decree (see sidebar).
What is the purpose of this document? The regulation has absolutely agreeable aims: to define the minimal quality standards required of organizations (or even single professionals), which will take over some of the GCP duties of the sponsor like monitoring or auditing trials. Given this positive intent, the practical application of the Decree is not an easy job.
Obviously, the facilities where CROs operate must be suitable and able to ensure secure filing of confidential documents. CROs are then expected to clearly list in writing all the services they provide. The ultimate "mission" of the organizations must also be stated, since it is required that CROs have a statute consistent with their activities. Up until this point, it was an exercise of basic common sense.
The Decree goes further. It mandates that each CRO have either a medical or scientific director with a degree in medicine or in congruent scientific disciplines and at least two years of professional experience.
With respect to quality requirements, it is naturally expected that CROs operate in compliance with GCP and that an SOP system is in place. This is, however, not enough. In fact, the Decree requires a quality system defined according to ISO norms, and to a quality manual or to "equivalent standards"—whatever those could be. Smaller companies could then have to face ISO 9001 certification.
A quality assurance director must also be present and must be reasonably seasoned. A degree is mandatory, as well as at least one year experience and 15 days of theoretical training in the last two years in the sector of quality assurance. The requirements for CRO personnel are where the companies will probably face most of the difficulties. Aside from generic requirements—like having both functional and nominative organization charts and adequate staffing for the services provided—it is also requested that CROs ensure at least 10 days of documented training per year for all staff, including external consultants. This is one of the most controversial requests of the Decree.
Ten days of training a year, the minimum routine training for certain CRO professionals, can be a very difficult target for less specialized positions. Training costs are then expected to significantly impact CRO budgets. Fortunately, the authorities have specified that internal training and participation in investigator meetings can be counted as training, but self-certifications are not accepted.
The Decree also covers professionals and technical workers who provide independent activities or consulting. After stipulating contracts with the sponsor of the trial or with a CRO to perform single functions referred to in the Decree, they must also satisfy the same requirements and must operate within the quality system of such structures.
Finally, the Decree presents some structural requirements for statistical and data management activities. For instance, the need to use appropriate and validated software and to have facilities and systems able to warrant the physical and logical safety of the data.
The Decree details specific requirements for monitors, auditors, and statisticians. It states that only adequately experienced and trained staff can be authorized to work autonomously. For example, a degree is now mandatory for monitors and auditors, while it was not in the past.
Once junior monitors or auditors start their professional career in a CRO, they must receive at least 10 working days of training within a year, on topics including methodology and regulations of clinical trials, GCP, good manufacturing practices, pharmacovigilance, quality, and quality assurance systems. The theoretical training must be followed by documented practical work in the field. At least 30 days of monitoring or auditing activities performed together with expert monitors or auditors are mandatory. In the case of monitors, tutoring must be performed for at least 50% of the visits at the clinical sites before a trial commences, during the trial, and after the conclusion of a trial.
Monitors (or auditors) should also have demonstrated previous experience in related fields. For example, they should have at least six months experience in the sector of control or surveillance of medicinal products or clinical trials within the last 12 months preceding the beginning of the autonomous monitoring activities—for auditors, previous experience as a monitor can also be accepted. A masters program in clinical trials, regulatory science or in an equivalent discipline can be an alternative for monitors. Whenever this previous experience is missing, it must be compensated by 60 additional days of monitoring or auditing activities together with expert monitors or auditors.
Only after these requirements are satisfied can monitors or auditors operate autonomously, maintaining their competence by participating in training programs on topics relevant to their duties for a total of at least 10 days a year.
The requirement for CROs performing statistical analysis and data management are also demanding. In this case, the CROs must have a qualified statistician who has at least either a degree in a statistics discipline, in an equivalent discipline or in a discipline of a scientific type coupled with adequate training in statistics or university specialization, a doctorate or a masters in a statistical discipline.
Key Requirements of the Decree
The qualified statistician must also have at least two years of experience on topics pertaining to their responsibilities. Annual refresher courses are needed as well.
Specific exceptions have been introduced for those individuals who were already working in CROs when the new Decree was introduced but who may not satisfy all of the new criteria—like those already working as monitors who do not possess a degree. Unfortunately, being granted an exception can be quite difficult.
For instance, monitors already working must ensure that during the 30 months preceding the release of the Decree (i.e., from October 1, 2005, to March 31, 2009) they performed at least 110 days of documented monitoring activities, of which at least 50% were carried out through visits to clinical sites. This means approximately two visits a month. Analog exemptions are set for existing auditors.
This retrospective demonstration can be very difficult for those who changed their company or for those who worked for companies that closed their business. And what about those experienced monitors or auditors who did not achieve the 110 days in that 30-month period preceding the release of the Decree? For example, women who were on maternity leave during that time. Unfortunately, the Decree seems to be very strict when defining the time windows when the experience must be demonstrated. An explanatory note released by the authorities in February 20093 states that an experienced monitor who for any reason has not performed at least 110 days of activity in those 30 months cannot benefit from the exemption and must demonstrate satisfaction in all the requirements of the Decree in full.
To continue to operate, the Italian CROs who were already compliant with the Decree had to provide notification by February 26, 2009, of the possession of the aforementioned requirements by means of self-certification. New CROs will have to proceed in the same way within 30 days before the start of activities (there are specific forms available on the AIFA Web site for CROs to fill out and list its specific activities and to state that it satisfies all the quality requirements of the regulation). The authorities will possibly conduct inspections to verify CRO declarations.
The sponsors of trials conducted in Italy that have contracts with Italian or foreign CROs that do not satisfy the requirements pursuant to the Decree will then have to face the risk that the results of the trials may not be taken into consideration by the authorities.
The CROs with headquarters outside of Italy that intend to carry out activities within the Italian territory must have legal representation in one of the member states of the European Union and must satisfy requirements that are at least equivalent to those set forth by the Decree. They will also have to send a self-certification to the authorities.
What will be the impact of the Decree? Indeed the Decree has the positive intent to set high standards for the work of CROs, however, the cost of implementation, especially for training, could be very demanding for smaller CROs.
Will foreign CROs be tempted to avoid trials in Italy to escape the additional bureaucratic burden? For example, will non-EU CROs set up a legal representative in one of the member states of the European Union just to carry out activities within the Italian territory?
What will the effect of the Decree be on young, inexperienced monitors or auditors? Will CROs be tempted to hire older, experienced professionals who could immediately be made operative instead of the less experienced to avoid the long introductory training required by the Decree?
What will happen to studies that started before the Decree? What if the CROs that were selected in the first place are now found not fully compliant with the Decree?
And finally, to what extent will the authorities be able to verify the compliance of CROs with the requirements of the Decree? How will this be possible for foreign CROs?
The Decree is now a few months old and all these questions will have to find an answer soon.
Mario Corrado is quality assurance manager at CROss Alliance, Via F.A. Giorgioli 14, Arzo, CH 6864, Switzerland, email: email@example.com
1. The Italian Agency of Medicines (AIFA), Italian National Observatory on Clinical Trials on Medicine (OsSC), 7th National Report on Clinical Tests of Medicinal Products on Clinical Tests of Medicinal Products (AIFA, Rome, July 2008).
2. Italian Ministry of Health, "Definition of the Minimum Requirements which Contract Research Organisations (CRO) Shall Satisfy in order to Work Within Clinical Trials on Medicinal Products," March 2008; Official Journal of the Italian Republic, 279 (November 2008), http://oss-sper-clin.agenziafarmaco.it/normativa/DM_CRO_English.pdf.
3. Italian Agency of Medicines (AIFA), "Question and Answers on the Decree 31 March 2008, Definition of the Minimum Requirements for CROs within Clinical Trials on Medicinal Products," II/11029/P-I.9.a.b/85, Rome, February 2009.