The Clinical Trials Directive in Portugal

For pharmaceutical and biotech companies wishing to operate on an international basis, a clear understanding of the different regulatory requirements across countries is critical. With the regulatory requirements constantly changing in different countries, however, keeping up to date is no easy matter. An important development in the European Union (EU) has been the adoption of the new EU Clinical Trials Directive (2001/20/EC),¹ which will affect all companies wishing to undertake clinical trials within the EU and has thus attracted considerable attention. The two primary objectives of this directive are to provide a more harmonized and structured European regulatory framework, and to ensure the safety of patients enrolled in clinical research.

Photography: Comstock, Photodisc Illustration: Paul A. Belci

Pharmaceutical industry in Portugal

Since its accession to the EU in 1986, Portugal has played an active role on the European stage, and was one of the first member countries to adopt the Euro currency in 1999. The pharmaceutical industry is considered a key sector by the Portuguese government, and in 2002, it publicly announced its desire to stimulate domestic industrial growth while encouraging international companies to base their businesses there.

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Around 130 pharmaceutical companies operate in Portugal and employ nearly 11,000 people.

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Health- care spending has nearly doubled since 1995, and the country has become an important pharmaceutical market.

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The emphasis on health care has also seen Portugal grow in importance as a center of clinical research, as pharmaceutical companies encourage physicians to gain more experience with their products.

The steady growth in clinical research is certain to be enhanced by Portugal's ongoing implementation of the Clinical Trial Directive legislation, which will ultimately streamline the submission approval process and running of clinical studies in the country, and significantly improve timelines to competitive levels.

Unlike the outgoing system in which ethical approval is obtained followed by regulatory notification, the new law establishes the necessity of obtaining authorization from both the Competent Authority (INFARMED)⁴ and ethics committee (EC) in order to conduct a clinical trial. Such authorizations can be submitted in parallel.

Transition period

The directive made provisions for a two-year transition period in order for it to be incorporated into national law, and one further year (until 1 May 2004) for final implementation. However, in Portugal as with some other EU member states, the directive timelines were somewhat protracted.

The legal text of the directive was implemented into the national legislation (Lei No. 46/ 2004) back in August 2004. However, the required guidelines for procedures have yet to be introduced, including the establishment of necessary regulatory and ethics infrastructures in order to apply the principles set out in the new law. Until recently, INFARMED implemented a transition period whereby clinical trial applications were submitted in a hybrid format. Now, INFARMED is receiving CTAs for full review, rather than notification. The transition period essentially involved following the current procedure of initially seeking ethics approval and then notifying INFARMED of the authorization together with a submission of the essential documents (including the EudraCT application form) as stipulated in the national EudraCT checklist. Incidentally, during this transition period, no additional national documents were required.

EudraCT, established in keeping with the European Directive, is a database of all interventional clinical trials of investigational medicinal products in the EU (registered after 1 May 2004), which records submissions made to both the Competent Authority and the EC. Sponsor entry can be made via the EudraCT Web site⁵ for the purposes of obtaining the necessary EudraCT identification number, gaining access to supporting documentation such as directives and guidelines, and for completing, saving, and printing electronic forms relating to clinical trial applications, amendments, and end-of-trial notifications.

Regarding this transition period, INFARMED published a circular (September 2004) declaring that if at least one ethics approval for a clinical trial was obtained before the implementation of the new procedures, that clinical trial would ultimately follow the current transitional system. One important requirement, article 4.1, is that the sponsor must register the clinical trial in the European Database⁶ and consequently obtain a EUDRACT number unique to that study.

Ethical review

Prior to the introduction of the new law, Portugal had three stages of monitoring with regard to ethical issues

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—the National Council of Ethics for Life Sciences (a consultative body), Centers of Reflection (for bioethical issues), and Health Ethics Committees, which review biomedical research. In order to ensure effective and efficient running of ethics committees, the Portuguese Ministry of Health recently published two official dispatches in which it established a higher grade of review known as the Ethics Committee for Clinical Research (CEIC) and the executive CEIC. Essentially, the executive CEIC will consist of seven members of the CEIC and will meet at least once a week. This new committee, which will be responsible for monitoring Health Ethics Committees in addition to receiving all applications for ethical review, will have the overall power to decide whether a clinical trial is deemed suitable to proceed, and will be responsible for fulfilling review timeline requirements as specified in the directive. For the most part, this board can assign a regional Health Ethics Committee to review the actual clinical trial application in question. In order to begin their activities, these two committees are awaiting final signed approval from the Minister of Health. It is anticipated that all procedures will be operating by mid-2005.

With regard to review timelines, under the new system, both authorizations will be issued within 60 days of submission, unless the tested drugs are gene therapy, somatic cell therapy or GMO-containing products. The timeframe for these types of products is 90 or 180 days, if an external group of experts is involved in the application review. However, if the tested drug is a xenogenic cell therapy product, there is no time limit for evaluation. In any case, INFARMED or CEIC can request additional information or clarifications to the application submitted if necessary. This request will be a single event, and there will be a clock stop in the time limits previously stated until the applicant submits the additional information or clarifications.

One of the main advantages of the new legislation will be that only a single opinion will be given by a central Ethics Committee. This is a notable improvement on the current system where EC submissions have been known to be rather cumbersome at times, with each hospital having different requirements that are not always well-specified. Indeed, there have been cases where a clinical trial had been authorized by an EC of one hospital within a month, only to be delayed due to extra review time required by other regional ECs. For example, one of the main hospitals in Porto had recently been without an EC for a number of months, thereby delaying the approval and subsequent initiation of the study at that hospital. Obviously this is not a common occurrence, but it illustrates how timelines sometimes depend on a variety of different circumstances.

Furthermore, a centralized EC will avoid particular preferences. Some sponsors and Contract Research Organizations (CROs) favored certain hospitals in the past, not necessarily based on scientific and quality criteria, but rather on the reputation these institutes have for speedy approval processes. It is therefore anticipated that the new timelines imposed by the directive will bring Portugal in line with the other EU member states, and will greatly enhance the country's appeal as a location for conducting clinical trials, a trend that is already on the increase.

Clinical trials in Portugal

Portugal itself boasts a high number of universities and central hospitals concentrated in major cities such as Lisbon, Porto, and Coimbra, with experienced staff to assist in the studies. Furthermore, most investigators from these hospitals will have significant experience in conducting clinical trials, and also an excellent command of English. Moreover, patient compliance is consistently good, and Portugal has proportionally higher recruitment rates than most other participating countries. One key factor for high recruitment is close follow-up from the very time the protocol is submitted for approval.

Another significant development in streamlining Portugal's clinical trial process has been the acceptance of Annex 13, the EU Directive standard guideline for labeling investigational medicinal products. This clearly will harmonize one aspect of how clinical trials should be undertaken and controlled. There had previously been significant differences in labeling requirements within each EU member state.

INFARMED recently implemented a fees structure associated with the regulatory assessment of pharmaceutical, preclinical, and medical data for applications for clinical trial authorizations. The fees have been estimated to reflect the time and resources required to complete the evaluation of applications and are categorized as follows: €1000 for Phases I to III, €450 for Phase IV, and €250 for bioequivalence studies.

Law no. 46/2004 also specifies the sponsor, investigator, and monitor responsibilities in the conduct of clinical trials.⁷ Likewise, it describes the terms of the financial contract between sponsor and site, such as direct and indirect costs, payment schedule, and any other conditions established between the parties.

During the course of a clinical trial, it may be necessary for the sponsor to make certain amendments to the clinical trial protocol. The new legislation makes provisions for this, and where amendments are considered nonsubstantial—where the scientific basis of the study is not altered or where the safety of the participating subjects is not compromised—only notification to INFARMED is required. In cases where substantial changes are made, CEIC and INFARMED approval will be required. Such approval will be issued within 35 days of submission. If objections are raised to the proposed amendment, the sponsor will have to adapt the protocol in accordance to those objections, or withdraw the amendment under consideration.

Under the forthcoming legislation, the manufacture or importation of investigational medicinal products (IMPs) are subject to authorization from INFARMED. Such authorization will be valid during the conduct of the study, and must follow good manufacturing practices (GMP). If the IMPs are coming from other EU Member States, such authorization from INFARMED is not required if the batches used are accompanied by the certificates of release issued by the qualified person and follow GMP or equivalent in accordance with the product specifications.

The new law also describes the type of fines (between €5,000 and €500,000) applicable in case the law is not followed, such as conducting a trial without CEIC or INFARMED approval, or conducting it in different terms than those approved, using IMPs outside the conditions of this law, giving incentives or financial benefits to participant subjects if not allowed by the law, manufacturing or importing IMPs without the appropriate authorization, etc. This system of fines will ultimately protect Portuguese patients in the unlikely event of medical malpractice. Another issue worth noting is that the rate of illiteracy in Portugal is still significantly higher than in some other European countries,⁸ and therefore emphasizes the need for stringent control of ethical practices.

Conclusion

Portugal has had, for some time now, a sound reputation as a leading player in the pharmaceutical arena. It has successfully positioned itself as an attractive country to conduct clinical research. The country has witnessed a significant increase not only in the number of industrial-sponsored trials, but equally within academic studies. The implementation of the Clinical Trials Directive with its accompanying regulations on good documentation and good clinical practice can only contribute to this upward trend, and will arguably put Portugal at a distinct advantage to a number of other member states that are barely at the early stages of implementing the directive. Considering the current changing environment, it is recommended to verify with INFARMED

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the status of implementation of the new law, and therefore the relevant requirements necessary to obtain authorization for the conduct of clinical trials.

Rory Gallagher*, PhD, is with the regulatory affairs department of Chiltern International, 171 Bath Road, Slough, UK, SL1 4AA, +44 1753 216695, fax +44 1753 511116, email: rory.gallagher@chiltern.com. Miguel ángel García, PhD, is with the clinical development department of Chiltern International (Portugal), +35 1 93 333 76 06, fax +35 1 21 760 60 96, email: miguelangel.garcia@chiltern.com.

*To whom all correspondence should be addressed.

References

1. Directive 2001/20/EC Of The European Parliament and of The Council of 4 April 2001.

Official Journal of the European Communities

. L 121/34. (2001) http://

europa.eu.int/eur-ex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf

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2. The view-point of Apifarma: The Pharmaceutical Industry as a Strategic Sector. Associação Portuguesa da indústria farmacêutica (APIFARMA) press release. 28th May 2002. (2002) http://www.apifarma.pt/noticias/?file=noticias_txt&cod=193.

3. Pharmaceutical Industry in Portugal. Agência Portuguesa para o Investimento (AIP). The Pharmaceutical Industry in Figures. Associação Portuguesa da indústria farmacêutica (APIFARMA) press release. (2004) http://www.apifarma.pt/menu/?file=texto&codigo_menu=2103&sel_men=2103.

4. O Instituto Nacional da Farmácia e do Medicamento (INFARMED): Apresentação. (2005), http://www.infarmed.pt/pt/instituicao

5. European Clinical Trials Database: EudraCT. (2005) http://eudract.emea.eu.int

6. Guideline on the data fields from the European clinical trials database (EudraCT) that may be included in the European database on Medicinal Products. European Commission: Enterprise And Industry Directorate-General. ENTR/CT 6. (2004) http://

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7. Portugal RECs and Medical Research. PRIVIREAL. (2004) http://www.privireal.org/countries/recportugal.htm.

8. Illiteracy in Portugal, www.portcult.com/Portugal.53_illiteracy_in_portugal.htm.