This reference tool from WHO lets investigators from any country speak the global language of medicine		

The Uppsala Monitoring Center's (Uppsala, Sweden) partnership with the UN-founded World Health Organization (WHO) allows the company to release electronic reference tools that trial sites around the world can use. 	

If a trial is running in several different countries, the drugs involved may have different names. This can be a potential problem for adverse event reporting. The WHO Drug Dictionary can ensure that the data from the trials will speak the same language.	

This reference tool goes beyond generic and innovator names. It lists every possible name for each drug, as well as a unique code. Therefore, your CRFs will be more easily understood around the globe. It contains over 45,000 names for almost 10,000 drugs, as well as over 16,000 different drug combinations.	

Information is added each quarter on new drugs, new indications and new adverse effects. An available DD History gives an audit trail of each drug's background, and a related Adverse Reaction Terminology product lets you know the proper taxonomy for any SAE in the world. For clients who don't need them all, UMC can do a custom search in the adverse reaction database, similar to Lexis/Nexus.	

Using embedded microchips, a subject's compliance in taking a pill is remembered by the packaging itself Information Mediary (Ottawa, ON) has done the next best thing to having a PI with a clipboard noting when each subject takes a dose of a study drug or placebo. When a pill is popped out of the foil packet, information is recorded on a  hidden microchip.		

The smart package works in place of other methods for recording when a subject takes a pill, ranging from stan-dard pen-and-paper forms to electronic methods using the telephone, a PDA, the Internet or a combination of methods.	

The Med-ic Smart Package contains a chip with sensors attached to each pill's container. They receive a timestamped message when the foil wrapper is punctured. The chip can also record humidity, heat, vibration and radiation, so the site will know if a subject stores medication on a radiator as well as if he or she is consistent in dosage compliance.	

 Med-ic Smart Packaging uses a popular new technology called remote frequency identification. The microchip in the empty pack transmits the timestamp when the subjects returns to the site. The chip is "read" by an RFID scanner similar to a supermarket barcode laser.  	

The same pharmacovigilant system that worked in Rockville and Brussels can work in Tokyo as well  Relsys International Inc. (Irvine, CA) offers a suite of Argus Safety pharmacovigilance software products to help make your eventual FDA and/or EMEA application trouble-free. One of the tools that sets the company apart is Argus J, which gives users the ability to send the same data that was generated for the United States and the European Union to the Ministry of Health, Labor and Welfare, Japan's regulatory authorities.		

English is the primary user interface for both Argus J and Argus Safety, but shadow and local fields in Japanese let the same fields double for MHLW authorities. Relsys was able to keep one database featuring both languages, instead of making a whole second database for a Kanji-character display. (Two databases mean twice the possible conflicts and errors.)	

Argus Safety offers options besides a database readable in Japan. Other features include an adverse event reporting system that supports Good Pharmacovigilance Practices, Oracle compatibility, and compliance with over a dozen different types of reports.	

Articles

News

The Uppsala Monitoring Center's WHO Drug Dictionary, Information Mediary's Med-ic Smart Package, and Relsys International Inc.'s Argus J

eShowcase

Trepidation and concern have been central to many U.K.-based discussions on the impact of the EU Directive on Good Clinical Practice in Clinical Trials.

 Some have suggested that the constraints imposed by the impending legislation may stifle innovation, leading to a reduction in novel academic research and the closure of some research centers. Other academic institutions are worried over increased costs of registering for any research project and of training the staff in good clinical practice (GCP). Many are also awakening to the implication of having one registered sponsor for each study who carries an exceedingly heavy administrative and legal burden.	

Admittedly, there are very big changes in store for the processes and cost of academic research and the good laboratory practice that must accompany it. Established research centers whose primary aim has been to promote good research with patient safety as their primary objective, however, have nothing to fear. The rigor of procedures and regulation has been with us for a long time. All that has changed in reality for an investigative unit such as ours is that our voluntary code of practice based on ICH, GCP 1996

 is now mandatory, and subject to the disciplines which any enforcement brings.	

As a dedicated clinical research unit for clinical trials and academic studies within a large London teaching hospital, we have been awash with in-house circulars, bulletins and documents, external journal articles, various training sessions, and meetings on how the directive will be making considerable changes to our working practices. There is a reminder from a symposium at the Medical Sciences Academy Forum (2003)

 that the directive will have a "profound effect upon us all." More recently still, The Institute of Clinical Research reported the concerns many researchers still had about the impact of the directive and how their processes might need to be radically changed.

 There is even a growing call for the EU Directive to be repealed.

 We are all unprepared. We need to be trained in the ICH Code, and trained as a matter of urgency!	

The code of practice was developed within the Expert Working Group of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), and the final draft was recommended for adoption to the regulatory bodies of the United States, Japan, and the European Union in April 1996. GCP is an international ethical and scientific quality standard for the designing, conducting, recording, and reporting of trials that involve human participation. Compliance with this standard provides public reassurance that human subjects in clinical trials will be protected and have their rights acknowledged and observed. Adopting the guideline also confirms some mutual agreement of any clinical data generated from a study by the regulatory bodies of those participating countries, thus strengthening any marketing application.		

Table 1. The 13 principles of ICH, GCP			

The EU Directive now seeks essentially to legalize all the principles of ICH, GCP for two distinct reasons. First, the protection of its citizens is of paramount importance. Second, there is a commercial intention within the directive to make Europe more competitive in the clinical trials industry. It is anticipated that this will be achieved by the harmonization of the clinical trials process and the standardization of regulatory body approval.				

This cannot come soon enough. Member states and indeed the United States have come under increasing competition from Eastern European countries such as Poland and Estonia, with their rapid regulatory submissions and speedy recruitment rates. Nevertheless, this drive to enhance clinical trials delivery has taken a long time. 	

The directive has at last come to fruition after 11 years of drafts, draft changes, a concept paper produced in 1995, and a draft directive in May 1996. It was approved by the European Parliament in December 2000 and published in the Official Journal of European Communities in May 2001. After publication, there is a period of three years to implementation (two years for member states to publish the appropriate legislation and one year to enact it). There are also numerous guidance notes prepared in consultation with the member states. To date, five of these have been finalized, and they include guidance documents for ethics committees (2003)

; collection, verification, and presentation of Adverse Events (2003)

; database on Suspected Unexpected Serious Adverse Reactions (SUSAR) (2003)

; and European Clinical Trials Database (EUDRACT) (2003).

 Still to be finalized at press time were the final version of the Good Clinical Practices,

 These will be written as two directives, which will automatically become law in all member states.	

The scope (Article 1) of the directive includes all clinical trials using medicinal products but does not apply to noninterventional trials and expands considerably upon the ICH, GCP (1996) guidelines. Their headings are listed in Table 1.	

Consider then the articles 3-5 of the directive: Protection of Clinical Trial Subjects, Trials on Minors, Consent in Incapacitated Adults, and the general emphasis and similarity to the ICH, GCP guidelines become clear-patient safety is paramount. When we conduct research we must respect the privacy, rights, and well-being of participants. This may seem a straightforward, almost automatic process, but it is so easy to forget the dignity and safety of research subjects. How often, for example, are obese subjects weighed in the corridor in full view of everybody, or inappropriate rooms used for physical examinations? Can we really be sure that subjects do understand the implications of the study before they give their consent? How often are unnecessary tests performed on these subjects?		

Table 2.  List of headings for the 24 articles in the EU Directive			

Although both the directive and ICH, GCP guidelines cannot truly measure this kind of patient dignity and rights, it is appropriate enough that the powers that be are allowed to audit any study for compliance around these issues. New regulations make unnecessary testing and repetitive studies obsolete because they will need appropriate peer review. It will become impossible to conduct studies upon those incapacitated adults who cannot give consent freely unless the study has already been conducted with subjects who can freely give consent. All studies will also need to be registered with the EU database before commencement.	

Our clinical research center will also be exploring our own practices and measuring service provision. Giving the research subject a voice improves the service for centers such as ours and assists us in the identification of our shortcomings. Perhaps the directive should include some mechanism for subject feedback. Auditors will also surely look favorably upon those centers that seek to gain insight into their practices by way of customer surveys.	

There is also another implication for our service expansion within the directive. Centers such as ours must therefore prepare for an increase in pediatric studies and ensure that the environment of the center, staff training, and clinical trial delivery is appropriate and sympathetic to the needs of children. In the past, pediatric clinical trials were by and large frowned upon because testing new drugs on children was thought unethical. This has led to a large number of untested drugs being used in many situations, which is also undesirable. The directive acknowledges this and has approved theory, which allows medicinal products to be tested if they are likely to be of significant clinical value for children.				

Although other articles also reflect the emphasis on patient safety through the data protection act and the reporting of Adverse Events, the remainder of the directive is concerned with the harmonization of the clinical trials process. In the United Kingdom, concerns exist over the increased organization of conducting a clinical trial. 	

For example, Articles 6-9 outline the responsibility of the ethics committee and the quality of the application, and gives time frames for committees to respond to applicants. Again, although there may be some organizational issues on how committees will be able to respond within the allotted time, the procedures for ethics submissions and the conduct of regulatory bodies has already been in working practice for a very long time in the United Kingdom, as defined by the Research Governance Framework for Health and Social Care.

 Apart from some agreed time frames for response, which is most welcome, there is nothing to panic the researcher in the directive. Even the ethics application has been recently standardized in the United Kingdom so that the same form will be used for both multiple and local submissions.	

Indeed, this directive is based upon the implicit assumption that many of the processes that involve clinical trials will be standardized, and the information shared on a common database. This standardization does not, however, translate well in the real world, and it is here that hospital research centers will need to act. 	

Research and Development Directorates, through which all research passes, must standardize their processes if the ethos behind the directive is to be upheld. It is here that common registrations of research projects, data protection forms, applications for indemnity, and the rules surrounding peer review would benefit from the same operating procedures across the board. Although some collaboration exists between sister hospitals, the directive would have done justice to most researchers if it insisted upon the uniform method of how new projects are presented to all R&D offices together with a time frame for when the researcher may get a response. Again, the Research Governance Framework gives guidance on R&D responsibility, but falls short of operationalizing the exact mechanism.	

In the United Kingdom, the amount of time that Lead Investigators may be allocated for research by way of the new Consultant Contract may be limited. A standardized pack of documents required by the R&D department and regulatory bodies will hopefully assist the beleaguered researcher through the clinical trials maze and may lead to an increase in business. Training of research center staff in the future will therefore include not only Good Clinical Practice, but also practical information on regulatory requirements and the exact documentation needed. It therefore makes good sense for our research center to further our own standard operating procedures by including this information and act as an additional advisory service to would-be researchers.	

We have acknowledged that it is the academic researcher who is hit the hardest by the directive. Vallance, in his recent article,

 establishes a real cause for concern among those conducting small clinical trials-especially pilot studies for funding application, mechanistic studies, and projects using existing drugs in clinical practice-that increased costs and bureaucracy will mean fewer projects being undertaken. Again, there is a certain amount of unwarranted fear. Concerns regarding what studies are and are not covered by the directive can be ascertained and clarified by the Medicines and Healthcare Products Regulatory Products. However, what is most certain is that the cost of noncommercial studies will increase substantially, and that for these types of studies to continue there will be a need to resource new research structures, train staff, and put in place the kind of standardized procedures just mentioned.				

The directive also requires the researcher to undertake a number of responsibilities when conducting a research study. Such responsibility is nothing new for clinical trials sponsored by the pharmaceutical community, but few in academic circles are willing to undertake the onerous task of being sponsor for their research project. Such tasks include ensuring the validity of the proposed project, undertaking all regulatory requirements, training the staff involved in the project, ensuring that there is sufficient resource to produce high-quality accurate data, and producing written agreement on responsibilities among the research group. There is also the provision of compensation, arrangements for disseminating the findings, and the dignity and safety of subjects to be upheld at all times.	

The lack of clear operational procedure for academics conducting their busy clinical workload and the onerous responsibilities they may face have implications for research centers such as ours. The center itself can become the "sponsor" for the project, ensuring all regulatory requirements, training, and resources are in place. It will be able to do this because most of the requirements are already there. But the service will come at a price, as we will need to increase our experienced research staff to meet the demand.	

The rate of enquiries to the research center from academics keen on undertaking new projects or wanting a "safe" venue for their existing study has already commenced and grown from an inconsistent drip to a steady trickle. There will be some fall-out among projects, but that may be good, for only the more robust will remain and attract the many funding opportunities which still exist. More researchers than ever are now aware of our center and what it can provide. It may not suit all projects, but our venue and the services we provide are being considered as never before.	

Researchers are also talking more to each other and listening to the voice of the R&D department. Research workshops have been organized, and for the first time ever the idea of a research strategy among directorates has been entertained, debated, and reported upon. The message from research strategy workshops organized by our R&D has been simple-we need to plan our research ahead to stay competitive.	

The general consensus of opinion may have been that the academic world failed to engage the European Union and its commissioners in the development of the EU Directive. At last it has woken up to the implication and decided to begin to work together with agencies such as the MHRA to form a coherent force, which will embrace the long research road ahead. For our unit, this is an exciting time to gain new business and be part of that cohesive force. To us, the directive is not saying anything new, and our established compliance puts us in a better position than ever before for undertaking the role of sponsor for academic studies. It provides a legal framework by which our unit may have input into the organization, planning, management, control, and accountability for an increased number of studies. We will develop our expertise to accommodate this anticipated request for our services. 	

EU Directive in Clinical Trials-bring it on!	

1. Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official Journal of the European Communities, L121, 34-44 (1.5.2001).				

2. ICH GCP official Web site contains all official documentation and is located at 		

3. European Clinical Trials Directive. A summary of papers presented at the Symposium organized by the Academy Forum on 3 June 2003, London. The Academy of Medical Sciences/Forum.	

4. A. Smith, (ed) "Repeal the EU Directive? Too Late," Clinical Research Focus, 15 (1) 4 (February 2004). 	

5. The campaign to repeal Directive 2001/20/EC, located at 		

6. EC Detailed guidance on the application format and documentation for application to Ethics Committees. Final April 2003, located at 		

7. EC Detailed guidance for the request authorisation of a clinical trial to competent authorities. Final April 2003, located at 		

8. EC Detailed Guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials. Final 2003, located at 		

9. EC Detailed guidance on the European database of suspected unexpected serious adverse reactions (Eudravigilance) Final April 2003, located at 		

10. EC Detailed guidance on the European Union Clinical Trials Database (EUDRACT) database. Final April 2003, located at 		

11. EC Detailed guidance on the principles of good clinical practice. Draft Version 5.1 July 2002, located at 		

12. EC Detailed guidance on trial master file and archiving. Draft. September 2002, located at 		

13. EC Detailed guidance on Inspection procedures for GCP compliance. No version, located at 		

14. EC Detailed guidance on qualification of Inspectors. No version, located at 		

15. Department of Health (2003) Research Governance Framework for Health and Social Care. DoH London UK. Located at 		

http://www.doh.gov.uk/researchgovernance/researchgovindex.htm

16. P. Vallance, "View from the Top: Small, Innovative Clinical Trials Are Under Threat," Research Fortnight, 14 (May 2003). 	

Feature Article

Trepidation and concern have been central to many U.K.-based discussions on the impact of the EU Directive on Good Clinical Practice in Clinical Trials.1 Some have suggested that the constraints imposed by the impending legislation may stifle innovation, leading to a reduction in novel academic research and the closure of some research centers. Other academic institutions are worried over increased costs of registering for any research project and of training the staff in good clinical practice (GCP). Many are also awakening to the implication of having one registered sponsor for each study who carries an exceedingly heavy administrative and legal burden.

A Perspective from One Clinical Research Center in the United Kingdom

The potential of the biotechnology industry to provide blockbuster products is clearly demonstrated by examples like Enbrel (for the treatment of rheumatoid arthritis in adults and of active polyarticular-course juvenile chronic arthritis), Remicade (for the treatment of rheumatoid arthritis and Crohn's disease), and MabThera (for treatment of stage III-IV follicular lymphoma and CD20 positive diffuse large B-cell non-Hodgkin's lymphoma). The EvaluatePharma database1 indicates that at least 265 biotechnology products are currently marketed globally, more than doubling the figure from 1995. It is clear that there are many more blockbuster products to come, with an additional 100 biotechnology products currently in Phase III/preregistration, and a further 1000 reported to be in active development.	

With this exponential growth in biotechnology product development, it follows that there is a corresponding increase in biotech clinical trial experience. Nevertheless, biotech clinical development continues to be a challenging exercise, particularly early on in anticipating the regulatory requirements for gaining approval to conduct a trial and in latter-stage clinical requirements for marketing approval.	

In biotechnology forums, it is sometimes said that biotechnology product development by small- to medium-sized companies (called small- and medium-sized enterprises or SMEs in the EU) will be leaner and more efficient than for traditional "big pharma" drug development. Although many accept this concept, the reality is that this hypothesis is yet to be fully tested. Of the more than 265 biotechnology products marketed globally, the vast majority have come from big pharma, and a significant proportion of the product candidates have come from SMEs. Due to the prohibitive cost of clinical development, however, the clear majority of products were partnered or licensed to big pharma. In the future, we anticipate that biotech product development by SMEs will continue to be leaner and more efficient than big pharma. For broad applications, the cost of clinical development will continue to require SMEs to partner with big pharma. But for rare and serious orphan diseases, there is an opportunity for SMEs to fulfill the promise of independent, lean, and more efficient drug development. 	

In this article, we aim to provide some insight into the clinical development of biotech products by outlining the regulatory requirements and highlighting some of the "hot" topics to consider when designing and implementing a biotech product development strategy. The focus of this article is biotech product development in the European Union (EU). However, with the continuing growth of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the principles discussed below have global significance.	

As more experience is gained with biotech product development, more and more guidance documents are being produced by both the EMEA (		

http://www.ich.org/UrlGrpServer.jser?@_ID=276&@_TEMPLATE=254

). From the EU perspective, two of the more significant developments include the publication of European Commission Directives 2001/20/EC

Harmonization of clinical trials regulations across the EU.

 Directive 2001/20/EC was published on 4 April 2001 and was expected to be implemented into Member State legislation by 1 May 2004. Given the existence of the ICH E6 Good Clinical Practice guideline, the purpose of this directive is to harmonize the EU regulatory approaches to the clinical development of medicines as much as possible, and in doing so help to ensure the confidence of EU citizens in medicine development. Some predict that the implementation of this directive will have serious repercussions on biotech product development. It certainly has the potential to increase the regulatory burden prior to initiating a clinical trial, particularly for early clinical development and investigator-sponsored studies. However, a more harmonized EU regulatory process should also help to make the requirements for conducting multicentric international EU clinical trials more transparent. Time will tell whether the goals of the directive are achieved.		

Table 1. Areas to consider for the first clinical trial application	

In accordance with Directive 2001/20/EC, all investigational medicinal products (IMP) in clinical development, even those in early development, will need to demonstrate Good Manufacturing Practice (GMP) in concordance with the phase of development, which will be a significant challenge for many independent investigators and start-up biotech companies. An additional regulatory procedure will also be introduced. Before submitting any documents to an ethics committee or to the national regulatory authority (defined in the legislation as a "competent authority"), it will be necessary to register with the EUDRACT database. This database is intended to facilitate both the exchange of information between the trial sponsor and the competent authority, the National Regulatory Authority, and between competent authorities of different Member States. To register in the EUDRACT database, it will be necessary for the sponsor to provide administrative information as well as information on the IMP, the trial protocol, and the envisioned countries and sites where the trial will take place. A unique EUDRACT identification number will then be allocated for each clinical trial entered by a sponsor, and this number will be requested for Ethics Committee and competent authority submissions. One benefit of this additional EUDRACT process is that the system may prefill for the sponsor the subsequent Ethics Committee and National Regulatory Authority trial application forms. 	

Once a sponsor has obtained the EUDRACT identification number, Ethics Committee and competent authority approval is still required. In practice, there are still likely to be differences between Member States, but overall it is expected that the process will be better harmonized. The applications for each will be very similar, including: 	

IMP Dossier (all Quality, Nonclinical and Clinical data on the IMP, and a integrated summary with an overall benefit/risk assessment)

Subject-related information (patient informed consent, recruitment methods)

Protocol-related information (where is the trial conducted in EU and outside EU, any other trials conducted with the IMP)

Manufacturing documents (GMP, TSE, Viral Safety, Certificate of Analysis)

Financial data (insurance, compensation, agreements, and contracts).

Time will tell what impact Directive 2001/20/EC will have on biotech product development.  While the goal is to better harmonize the regulation of clinical trials in the EU and help to ensure the safety of trial participants-both significant benefits-it remains to be seen whether it will place unrealistic demands on the heart of the biotech product pipeline, the independent investigator and biotech incubators.	

Additional guidance on marketing approval requirements in the EU.

 While seeking marketing approval can seem a distant target, even in early product development, it is wise to consider what will need to be included in the marketing application, when this data will be generated, and how it will be presented. Directive 2001/83/EC, published on 6 November 2001, is the legislative basis for the regulation of marketing products in the EU. 		

Table 2.  Overview of nonclinical testing of three approved monoclonal antibodies	

Annex 1 of this directive provides detailed description of the content and format requirements of a marketing application. Directive 2003/63/EC was published on 25 June 2003 in order to update aspects of Directive 2001/83/EC. This update was in part motivated by the development of the ICH Common Technical Document, but also to address advancements in biotechnology that have led to the development of products based on antibodies, genetically modified organisms, and cell therapy. It is a significant step forward, answering many questions on what data is typically required and where it should be included in the marketing application dossier for a biotechnology-derived product. Review of Directive 2001/83/EC is ongoing, with additional revisions expected to be finalized by the European Parliament during the first half of 2004 (updates on the progress of the new legislation are published at 		

http://pharmacos.eudra.org/F2/review/index.htm

While both of these documents help to clarify the regulatory requirements for conducting a clinical trial and for clinical development of a product, biotech product developers are still frequently frustrated by the expressions "case by case" and "scientific-based approach." While this uncertainty can be unsettling, as illustrated in the following lessons, it does provide opportunities for biotech product developers to negotiate with the regulatory authorities using scientifically based arguments.	

Biotech clinical trial application lessons 

Below are some examples of issues that can often cause delays in the clinical development of biotech products and are likely to become increasingly scrutinized by regulators as Directive 2001/20/EC is implemented.				

Lesson #1-Data requirements for conducting the first clinical trial.

One of the more difficult decisions when developing a biotech product candidate is the compilation of the first clinical trial application. While there are some guidance documents available, such as the ICH S6 Safety Studies for Biotechnological Products, there is a need for a "case-by case" and "scientific-based approach." In our experience, there are two areas that most concern regulators, as indicated in Table 1.	

Devising an appropriate nonclinical development program can be challenging for biotech products, because the required studies depend on the nature of the product and the condition it is being developed to treat. This is the basis for the dreaded expressions "case-by-case" and "scientific-based approach." While this scenario is challenging, it can also provide opportunities. A common mistake is to perform the traditional battery of nonclinical testing thinking that performing additional unnecessary studies is preferable to not performing enough. However, such an approach is not recommended because performing unnecessary tests such as toxicity testing in an irrelevant species can provide misleading and damaging data. Table 2 provides an overview of the nonclinical testing of three approved monoclonal antibodies and shows that a tailored "case-by-case" and "scientific-based approach" is acceptable to regulators. Each of the three products had minimal pharmacokinetic, pharmacodynamic, and toxicity programs since it was felt that a full traditional approach was not appropriate. 	

The key to Lesson #1 is to create a development plan based on sound science, which is then validated with leading experts in the relevant fields. This development plan can then be further validated with regulatory authorities, either by meetings with national authorities or by seeking scientific advice (or protocol assistance if the product has an orphan indication) from the EMEA. This approach ensures that your product is represented in regulatory submission in the best possible manner and therefore helps to avoid regulatory delays.	

 The demonstration of viral safety is becoming increasingly important for biotech products, with some EU regulatory authorities, such as the French agency (AFSSaPS), currently requiring a specific "Viral Safety Application" to be submitted before conducting a biotech clinical trial.  	

Viral safety is particularly pertinent to vaccine development, where the active substances traditionally are isolated viral or bacterial antigens, or more recently have been based on recombinant proteins or live attenuated viruses/viral particles. In these cases, the risk of propagating foreign viruses and of incomplete activation of the intended viral-based active substance must be addressed. The host cells may have a latent or persistent infection; for instance, a retrovirus that may be transmitted vertically from one cell generation to the next, and which may be expressed intermittently as an infectious virus.4 Adventitious viruses could also be introduced in the production process by the use of contaminated animal products. Special precautions therefore have to be followed to prevent the contamination of the final product with potential dangerous impurities, including retroviral contaminants and the possibility of contamination with DNA. 	

Taking into account the above considerations, evidence has to be provided that viruses are either inactivated or eliminated during the process of production. Different strategies to demonstrate the elimination of foreign viruses can be used depending on whether the vaccine contains a live virus, inactivated virus, or viral or bacterial antigens. Typically, the ability to remove/inactivate viruses during the production process is shown by spiking the drug substance before critical purification steps with a known number of different viruses. The efficacy of the purification step is then shown by the reduction of viral count. Frequently, small nonenveloped viruses, large enveloped RNA viruses, and large DNA viruses are used in such experiments.

While such tests and experiments have only an indirect influence on clinical development, as the design of clinical studies is not influenced by these investigations, the viral safety program may have a major impact on the timing of the clinical development. To avoid regulatory delays, the viral safety studies should be performed early during process development, prior to the start of the clinical development of the product. In accordance with Directive 2001/20/EC, all countries in the EU have a responsibility to ensure that each clinical trial product lot is evaluated with respect to its manufacture and planned indication prior to its use in a trial. Experience shows that the issue of viral safety will be carefully evaluated by the authorities.	

 Genetic engineering is obviously an important foundation of biotech products, and the regulation of such technology in the EU is the subject of considerable debate. Fortunately, the use of this technology in the development of medicinal products is currently less contentious than in agriculture. However, an assessment of the environmental risk posed by the manufacture and use of genetically engineered medical products must still be carefully considered. For example, many developmental vaccines are based on attenuated or genetically modified organisms (GMOs), and special consideration has to be given to the release of these organisms.

 In these circumstances, the manufacturer must provide data demonstrating the risk a GMO may represent in nature, including evidence that the live organisms do not revert or recombine to de novo pathogenic strains.	

An excellent case study is a live oral cholera vaccine, which is approved for marketing in a number of countries, including Switzerland, Australia, East Asia, and Latin America. During the development of this product, the excretion and survival of the vaccine strain in the environment was investigated in order to address potential environmental risk concerns. Studies demonstrated that up to 12% of vaccinees shed the vaccine strain at very low titres (6 logs lower than what the vaccine contains). The capacity of the vaccine strain to survive in the environment was subsequently found to be similar to the wild-type strain.

 As the wild-type strain of V. cholerae is known to enter a "viable but not culturable" (VBNC) status

 it was necessary to demonstrate the vaccine strain does not have an increased ability to go into the VBNC status (i.e., that a "super" strain has not been inadvertently created).	

Serologically, the vaccine strain cannot be differentiated from the wild-type strain. Therefore, a marker gene was inserted into the genome of the vaccine strain.

 The environmental risk assessment included evidence that the inserted mercury resistance gene did not represent a risk as the gene: 1) is expressed by Shigella bacteria, 2) was stably inserted into the genome of the vaccine strain, and 3) no evidence was found that co-culture of the vaccine strain with other bacteria could result in the transfer of the marker gene to other bacteria strains.	

Genetic stability with respect to the pathogenic capacity of the vaccine strain was also demonstrated. More than 90% of the cholera toxin gene was excised by genetic engineering. First, all transfection experiments performed in vitro showed that the vaccine strain has no capacity to revert to the toxin-carrying strain, and can therefore not spread the disease in parts of the world where it is not endemic. Secondly, the genetic characterization of shed bacteria revealed no capacity to take over genetic information from other bacteria growing in the intestine.

Unlike viral safety (described in Lesson #2), environmental risk assessment has a direct influence on the clinical development of vaccines containing live bacteria or viruses. Clinical studies must be designed to allow the evaluation of the shedding kinetics and the vaccine bacteria/virus should be tested genetically after passage through the intestine. Evidence must be provided to demonstrate the ability of the shed vaccine bacteria/virus to survive in the external environment and the subsequent potential impact on the external environment.	

Regulatory guidance and case studies do help. However, biotech drug development will always be a challenging task because rarely will a development be repeated. New challenges and obstacles will inevitably arise with each development, even though this environment does provide opportunities for those who respect the regulatory requirements and apply strong scientific and ethical principles. The continued application of biotechnology to address orphan diseases provides a true opportunity for the biotechnology industry to fulfill the promise of lean and efficient drug development.	

1. EvaluatePharma Integrated Pharmaceutical Company Information Service, 		

2. Directive 2001/20/EU. OJ 2001; L 121:34-44 (available at 		

http://pharmacos.eudra.org/F2/eudralex/vol-1/home.htm

3. Directive 2003/63/EC. OJ L 159: 46-94 (available at 		

4. CPMP/SWP/4447/00 draft: Note for guidance on environmental risk assessment of medicinal products for human use.	

5. CPMP/BWP/268/95: Note for guidance on virus validation studies: The design, contribution and interpretation of studies validating the inactivation and removal of viruses.	

6. Directive 90/220 EEC. OJ 1990; L 117: 241-262.	

7. Directive 2001/18/EC, OJ 2001, L 106: 1-38.	

The potential of the biotechnology industry to provide blockbuster products is clearly demonstrated by examples like Enbrel (for the treatment of rheumatoid arthritis in adults and of active polyarticular-course juvenile chronic arthritis), Remicade (for the treatment of rheumatoid arthritis and Crohn's disease), and MabThera (for treatment of stage III-IV follicular lymphoma and CD20 positive diffuse large B-cell non-Hodgkin's lymphoma). The EvaluatePharma database1 indicates that at least 265 biotechnology products are currently marketed globally, more than doubling the figure from 1995. It is clear that there are many more blockbuster products to come, with an additional 100 biotechnology products currently in Phase III/preregistration, and a further 1000 reported to be in active development.

Anticipating New Regulatory Hurdles

New requirements for clinical research teams, and administrative responsibilities and constraints for investigators conducting noncommercial trials.


On the 1st of May, the Directive 2001/20/EC on clinical research became law across the 25 member states of the European Union.

 This directive covers a wide sweep of issues on interventional trials which have implications for clinical research teams, including the suitability of investigators and the quality of facilities, informed consent, ethics committees, noncommercial trials, and the European clinical trials database (EUDRACT).

In this article, we will concentrate on the practical implications of new issues that this directive will bring to clinical research practice at investigative sites. We will also discuss noncommercial studies where investigators will be obliged to fulfill the responsibilities of sponsors.


The directive has introduced the dimension of the suitability of investigators, their supporting staff, and the quality of facilities into the practice of clinical trials across Europe. This is a welcome initiative giving new importance and consciousness to the conditions in which clinical trials will be carried out and managed at investigative sites. It is well known that there are great differences in standards of facilities, which vary in size, expertise, and organization.

Training of investigators and clinical research teams.

 Principal Investigators will be legally required to send their qualifications and any GCP training or experience obtained from work with clinical trials to the local ethics committees for opinion on their suitability to conduct clinical trials.

Such individual and group training is a major factor. Emphasis is being placed on theory and clinical trial practice. Investigators may have clinical knowledge, experience, and renown in the pathology under study, but too few have training in the theory of good clinical research practice. This is relevant because as of 1 May some investigators will be undertaking the responsibilities of sponsors for noncommercial academic trials.Investigators and their supporting staff will need adequate protected time for training. Details of training sessions must be recorded by the investigator and the members of the research team.

 Clinical investigative sites will be required to submit to the local ethics committee an evaluation of the quality of the facilities (including the availability of adequate resources, personnel, and laboratory facilities) in which they plan to conduct a clinical trial. At present, many clinical investigative teams perform clinical trials in clinics and inpatient facilities that do not meet the adequate privacy environment standards required by the directive. 

Informed consent and protection of subjects


The directive has reiterated the basic requirements of informed consent, which are already detailed in the Guidelines of GCP CPMP/ICH135/952 and the Declaration of Helsinki.

There are two new areas that will have practical implications for investigative teams. First, the increase in the amount of information to be given to clinical trial subjects; and second, the protection to be accorded to children and adults incapable of giving legal informed consent. 

Additional information to be given to clinical trial subjects.

 Subjects will have the right to know the name and address of the sponsor, the institutional affiliation of the investigator, the financial ties between the investigator and the sponsor, the source of finance for the study, and contact details of all personnel involved in the trial. 

 The Directive 95/46/EEC already deals with general safeguards to subjects privacy and protection of personal data.3 The new directive, however, is clear on matters affecting subjects in clinical trials; for example, that they should be informed who will access their clinical trial data, the procedure for handling any retained identifiable biological samples, and plans to anonymize or destroy samples after analysis. 

The practical implications for clinical research teams will be that the documents of information for subjects/patients will be long(er) and (even more) detailed. It is likely that there will be need for more than one consultation with a potential participant, parent, or legal representative to allow for the giving of information, discussion, and reflection. If there is a pharmacogenetic component to the clinical trial, investigative site teams will need adequate time to explain clearly to the participants the background and purpose of any genetic tests, the planned analyses, whether the samples will be kept for future analyses, and the fact that he/she may abstain from the genetic testing but still participate in the main part of the trial. This will take time, which will surely be a source of difficulty for investigators who seek to enroll patients in clinical trials in emergency departments or the intensive care setting.

 Clinical research teams will need to have written procedures for the management of persons responding to advertisements. Advertisements must contain information, which may include, for example, the nature of the project, type/group of subjects who might be included, and the fact that the subject will be placed on a volunteer register. Investigative site teams will need to follow formal advertising regulations, which will require more complete information in advertising notices. This will require more resources being available for that purpose.  

Person incapable of giving legal consent.

 Formerly, investigators were not obligated to describe the procedure for obtaining informed consent from a patient or his legal representative, the process being an informal voluntary code of (ethical) practice by a physician/investigator wishing to offer treatment to his/her sick patient in a clinical trial. This has now been formalized into a more standardized procedural approach, which will make investigators and clinical research teams more conscious of their responsibilities towards persons incapable of giving legal informed consent.

Two sets of information sheets may be required. In addition, information must be given to the subjects parent(s) or legal representative, and the subject will be given information according to his/her capacity to understand. The procedures to obtain assent/consent from the patient as well as from the parent or legal representative should be described in the protocol. In addition, during the clinical trial there will be a need for constant surveillance to assess the ability of these patients, to confirm or withdraw their participation in the study.


Ethics committees received particular attention in the directive in a bid to standardize their administrative functioning across the European Union. From the practical perspective of investigative sites there will be the introduction of the single opinion and clear timelines within which sponsors and the ethics committees must operate.

 There will be a single national ethics committee opinion in each Member State for proposed multicenter trials. The concept of Single Opinion already functions in some European countries. However, in other countries, such as Belgium, where the Single Opinion system will be newly established, there will be both local and the new national ethics committees. Investigators or sponsors (the directive does not specify who) will be obliged to submit documentation to both committees. This will increase the administrative burden for clinical trial sites. In addition, where both the national and local committees exist, there will of course be the possibility that local ethics committees reject the study or amendment, etc., at specific sites. This situation might delay the start of a study or the implementation of an amendment by a site or a country during discussions to reach agreement.

For single-center trials, the principal investigator will submit the appropriate documentation to the local ethics committee. For multicenter trials the coordinating investigator will be responsible for the submission of documents to the national ethics committees, and investigators at site level may submit these to their local ethics committees.

Response times from ethics committees (and competent authorities).

 60 days, with an extension of 30 days if there is a request for further information. 

 35 days for the EC; the CA may extend this if it wishes further information.

The advantage of such centralized national systems is that, with the timelines set down for the responses by ethics committees, there will be less delay in the commencement of clinical trials across Europe. At present, some countries have to wait many months for approval from their ethics committees, while their neighbors have approval within weeks and very obligingly go ahead and polish off the recruitment. This leads to a sense of frustration at investigative sites waiting for approval and delays the overall recruitment for the sponsors. 

Many investigative sites (including our own here in Belgium) have benefited from ethics committee rapid response, thus having an advantage over others dependant on slower response approval systems. 

Information to be notified to ethics committees.

 The application form has two modules (the first is the same as that for submission to the competent authority). There will be a considerable increase and detailing in the information to be submitted, though this may vary between countries. In commercial trials, sponsors will collate all this information. 

When an academic noncommercial study is involved, the principal/coordinating investigator acting as sponsor has these responsibilities (see list of administrative responsibilities).

At this time, there are many clinical investigative sites (like ourselves) that perform both commercial trials with the pharmaceutical industry and noncommercial (academic) studies alone or in collaboration with other investigators.

The directive recognizes that noncommercial clinical trials conducted by researchers (without the participation of the pharmaceutical industry) may be of great benefit to patients. However, after May 2004 no intervention research may be initiated without a sponsor, defined in the directive as an individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trial. This means that investigators who wish to perform clinical trials without commercial backing must themselves become the study sponsors. The administrative responsibilities will be exactly the same as those of the pharmaceutical industry for commercial trials.

There has been much commentary on this issue over recent months, and it is indeed a very new area for the investigative site teams involving administrative and legal constrains and responsibilities.

The coordinating investigator with new sponsor responsibilities.

 A new function, the coordinating investigator, has emerged from the directive. From the perspective of the clinical research team, the practical implications of the above are: 

 In the case where ones center is involved in a multicenter, noncommercial study as an investigative site, then there is no additional responsibility.


 In the case where a single center is conducting a noncommercial study, the principal investigator of the study will fulfill all the responsibilities of sponsor.


 In the case of a single-country, multicenter, noncommercial study, a coordinator will be chosen from among the participating investigators. This coordinating investigator (who will most likely also be the principal investigator) will have the responsibilities as sponsor of the study and the coordination of the principal investigators at different sites. 


 In the case of a multinational, multicenter, noncommercial study, a national coordinating investigator will be chosen in each country from among the participating investigators. This national coordinating investigator will have the responsibilities of the sponsor of the study in his/her country and will be responsible for the coordination of the principal investigators at different sites in that member state. In addition, he/she will be the national contact person for the study. If ones center is also that of the coordinating investigator (single country, multicenter trials), or national coordinating investigator (multinational, multicenter trial) then quite apart from the clinical and administrative conduct of the study (as a site), there are additional administrative responsibilities of a sponsor and the coordination of the work of the principal investigators of the other sites.

 Noncommercial trials will be carried out using either marketed or investigational medicinal products. For trials using marketed products, things will not essentially change from the current practice of using commercially packaged and labelled medication if they are used within the guidelines of the 65/65/EEC directive on authorized medication (this is a favor by the directive to the sponsors of noncommercial trials).7 Investigators using investigational medical products will be taking on major responsibilities and costs. These drugs will have to be produced by a manufacturer certified to good manufacturing practice (GMP) standards that must respect the legal obligations on manufacture, packaging, and labelling.

Monitoring of investigative sites in noncommercial trials.

 This is not specifically mentioned in the directive, but as the validity of data or the clinical research practice must not be doubted in these studies, systems must be put in place by the principal/coordinating investigators for the monitoring of the clinical, logistical, and administrative data at investigative sites. There is also the issue of recording and reporting adverse events during the clinical trial. Suspected Unexpected Serious Adverse Reactions (SUSARs) for both commercial and investigational medicinal products must be reported within strict timelines to other investigators, ethics committees, and competent authorities, so systems must be in place for verification that these obligations are being respected. As with commercial studies, the principal investigator/sponsor will need to produce yearly/final reports for the ethics committees and competent authorities on their noncommercial trials. They will require up-to-date reliable data.

How are investigative sites to find appropriate financing?

 After 1 May, there were major changes when the administrative and legal obligations became exactly the same for commercial and noncommercial studies. How are investigative sites that rely on public funding to find the money? Until now, investigative sites (like ourselves) have had relatively little difficulty in setting up and performing noncommercial trials, especially when they were done within structures that were already staffed and equipped for clinical trials. 

There will be need for trained personnel and suitable facilities. There will be high costs for the insurance necessary to cover participants in these studies. If investigative drugs are being tested, there will be the expenses related to its manufacture, labelling, and packaging. Studies will need monitoring to ensure the integrity of the data and the conduct of the study. Finally, there will be need for an accountant to keep track of the finances in such an enterprise. Cash flow and solvency will be matters of earnest interest to the investigator thinking of undertaking a noncommercial trial in the future.


This section deals with the responsibilities of sponsors, which will be identical in both commercial and noncommercial studies. Principal/coordinating investigators (and their clinical research teams) who will fulfill the responsibilities of sponsors of noncommercial academic studies need to be aware of their administrative and legal obligations in order to comply with the new accountability at the national and European level. This indeed is the point where the academic research community will find itself seriously challenged.

(Principal/coordinating investigators who undertake the responsibilities of sponsors in noncommercial trials will be noted as sponsors in the following sections.)

Practical applications of sponsors administrative obligations. 

 In practice, the sponsor will be responsible for the following (nonexclusive):

 Writing the protocol incorporating the new requirements of the directive 

 Writing the subject information and informed consent documents incorporating the new requirements of the directive 

 Submission of the study and documentation to the national ethics committees

 Submission of the study and documentation to the competent authorities of the member state

 Submission of substantial amendments to the national ethics committees and the competent authorities

 Reporting of SUSARs to the ethics committees, the competent authorities, and other investigators (if multicenter trial). This is the case for both investigative products and medication with marketing authorization

 Submission of annual reports to ethics committees and the competent authorities

 Submission of End of Study notification to the ethics committees and the competent authorities

 Submission of End of Study reports to the ethics committees and the competent authorities

 Response to the ethics committees and the competent authorities of any clarifications that may be requested.

Steps in the notification of a clinical trials.

 The sponsor must register with the EUDRACT database (via the Internet).

 The sponsor then obtains a EUDRACT number. 

 The competent authorities (by the coordinator investigator/sponsor) and the ethics committee (by the coordinator sponsor or investigator) will be notified of the studythis can be done in parallel or sequentially. (After receiving approval of the study by the ethics committee, the competent authority will complete this information in EUDRACT at the beginning of the trial.)

 The sponsor has the obligation to assess if an amendment is substantial, meaning that it could have a significant impact on the safety or the physical or mental integrity of the subjects, the scientific value of the trial, the conduct or management of the trial, the quality, or the safety of any investigational medicinal product used in the trial. Substantial amendments must be submitted to the competent authority, the ethics committee, and the other investigators. The application form, which should be used, is common to both. 

The principal investigator in single-center trials or co-coordinating investigator in multicenter trials should sign the substantial amendment. Amendments may not be implemented without a favorable opinion of the ethics committee and the competent authorities. In cases of changes consisting of urgent safety measures to protect the trial subjects, however, the sponsor should inform the ethics committee and the competent authority as soon as possible after these measures have been implemented.

The sponsor need not notify nonsubstantial amendments to the ethics committees or the competent authorities. These should be recorded and be available on request for inspections at investigative sites and at the sponsors offices. This is surely the only example in the directive where, compared with current practice, there will be a lessening of the administrative load at investigative sites.

It is clear that clinical investigative teams will need to adapt to the new status of noncommercial studiesall studies are the same in the eyes of the law in Europe after 1 May 2004. 


It is an objective of the Directive 2001/20/EC that inspections will be carried out to determine compliance to the laws on clinical trial practice. Most clinical investigative teams have at some time had an inspection for ongoing studies, or those that have been completed. Soon these inspectors will be from Europe too. We had no further information at press time.

 At this time, the signal from the European Medicinal Evaluation Agency is that the investigator site file is under evaluation, and a document is expected in future months. 


What are the conclusions on the practical implications of such a directive for clinical research teams? The first is that there is now a long overdue legal framework for participants and personnel on the practice of clinical trials in Europe. There is also new accountability and control of the practice of clinical research at investigative sites.Participant protection is a clear winner, as evidenced by the increased information that must now be provided to participants of clinical trials, and the necessity for detailing administrative and study management procedures in the protocol.

The directive will raise and standardize the practice of clinical trials between investigative sites across Europe, making it a safe and sure place for practice of commercial and noncommercial studies.

Noncommercial academic studies will now be on the same legal and administrative level as those sponsored by the pharmaceutical industry. The funding of these studies is uncertain. Only highly organized, specialized centers of excellence with a highly professional sponsor mindset will be able to obtain funds for the most scientifically original and relevant studies. 

Applied Clinical Trials-05-01-2004

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