With the rapid geographical expansion of clinical trials, industry professionals are increasingly willing to set up studies in exotic locations. Although their initial concerns about the quality of data from far-flung studies have dissipated, debate continues about the ethics of performing trials in new locations, especially in developing nations.			

India is among the group of countries hosting an ever-increasing number of new studies. This is no surprise, given that its population exceeds one billion, giving it the potential to lay claim to every sixth subject in the world. The increase in highly trained investigators, together with regulatory investment and restructuring, will further boost India's attractiveness to the clinical trial industry. Clinical trials in India are here to stay.	

Currently, about 80 government and privately owned Indian hospitals are engaged in global and local clinical trials. Observers predict that this figure will increase exponentially in a country with an estimated 14,000 hospitals, 500,000 doctors, 700,000 beds, 162 medical colleges, and 17,000 medical graduates per year.				

A study by the global consultancy firm Ernst and Young revealed that the total market value of clinical research performed in India between 1991 and 2001 was an estimated U.S. $70–$80 million. The firm attributed the increase to large subject pools in most major therapeutic areas, improved medical infrastructure, increased awareness of the ICH Guideline for Good Clinical Practice, and formation of a specialized pool of research investigators.	

Increased awareness of good clinical practice (GCP) requirements and a strong desire for international acceptance of their research have brought positive changes in the attitudes of clinicians all over India. Investigators, most of whom have been trained in Western Europe or the United States, are now consolidating their extensive research experience base and are eager to show the world that India can accommodate large clinical studies.	

Participation in multinational studies confers increased status upon a clinical investigator, providing an additional incentive for investigator participation and dedication. Compared with their European colleagues, Indian investigators tend to have fewer conflicting protocols competing for the same subject pool. India announced in December 2001 that all pharmaceutical clinical research must strictly follow government-issued GCP guidelines. These guidelines were formulated by an expert committee set up by the Central Drugs Standard Control Organization in consultation with relevant experts. Consequently, the level of research and ethics in some institutions is now on par with European standards.	

Recent increased interest in clinical trials in India has led to a number of clinical research organizations (CROs) opening up offices in India.		

 Because of the increased number of multinational trials being conducted in India, the Indian Government has proposed an amendment to Schedule Y of the Drugs and Cosmetics Act. The act, which governs product registration and the conduct of clinical trials in India, originally stated that there must be a phase lag of early phase clinical trials between India and the rest of the world. In other words, that means that India should not be the world's proving ground for untried therapies.	

The implication of the amendment to Schedule Y is that the government will allow, on a case-by-case basis, foreign sponsors to include India in global multicenter Phase 1, Phase 2, and-subject to further approval-Phase 3 trials. However, to ensure that Indians are not the only ones exposed to a new drug, permission will not be granted to foreign companies for trials conducted exclusively in India.	

Government officials also have decided to bring rDNA products under Schedule Y. This is a new area of research, and detailed guidelines are being prepared. These are based on the existing guidelines of the Department of Biotechnology for generating preclinical and clinical data for rDNA products. With the government of India taking a formal view of the Schedule Y amendment, trials will be monitored appropriately in tandem with checks and controls to address ethical concerns. This initiative of the Drugs Controller General of India (DCGI, or DCI) is supported by the World Bank and is intended to strengthen DCI's control of the drug development procedure.	

 The  majority of patients are treated in the 4000 government-funded or -subsidized general hospitals, 80% of which serve the urban population (accounting for a quarter of the country's population). The remaining 20% serve the rural population.1 These government-funded and/or government-subsidized hospitals offer the best setting for clinical research. Most hospitals are linked to teaching institutions with modern facilities and well-qualified, trained staff. These hospitals tend to be very large, with hundreds of inpatient beds.	

The relative cost of Indian health care is still very low compared with that in Western nations. Additionally, a large pool of private practitioners and specialist-run private health care facilities are always keen to be involved in clinical trials.	

Medical and public health matters, including the control of drugs and the prevention of food adulteration in India, are under the control of the Ministry of Health (also known as the Department of Health). The secretary to the government of India heads this department and is supported by two deputy secretaries; they, in turn, are supported by the Drugs Controller of India. The DCI's office is responsible for the approval of manufacture, marketing, and clinical trial applications.		

The DCI's office is also responsible for the overall functioning of a variety of regional units spread across India, and for the management of blood banks and vaccine units. These regional units, which include zonal offices, subzonal offices, port offices, and laboratories, all report to the DCI. Four zonal offices and three subzonal offices of the DCI are responsible for coordination between the state and the DCI. The two entities conduct joint inspections of manufacturing plants, blood banks, pharmacies, and so on. The main zonal offices are located at Mumbai, Kolkata, Ghaziabad, and Chennai. Subzonal offices are located at Ahmedabad, Hyderabad, and Patna (which is closed at the moment). The main functions of the DCI's office include, among others:	

Transfer of licenses between joint venture partners.

Good manufacturing practices (GMP) and good clinical practice (GCP).

Regional monitoring and implementation of the Drugs and Cosmetics Act.

Collaboration with the pharmaceutical industry for exports.

Inspection and implementation of GMP at manufacturing plants.

Coordination with Department of Biotechnology (DBT), National Institute of Biologicals (NIB), Indian Council of Medical Research (ICMR), and so on.

Port offices are responsible for clearance of products that are imported into the country either for marketing purposes or for clinical research. Samples are randomly selected and sent to the Central Drugs Laboratory (CDL) for testing. The CDL is the national statutory laboratory of the Indian government. It is responsible for the quality control of drugs and cosmetics in accordance with the Indian Drugs and Cosmetics Act of 1945. India has six National Laboratories situated in Kolkata (Calcutta), Mumbai (Bombay, which has two), Ghaziabad, Chennai (Madras), and Ranchi. Their functions include	

conducting analytical control of imported foreign drugs (both bulk drug and finished formulations).

conducting analytical quality control of drugs and cosmetics manufactured within India on behalf of the Central and State Drug Control Authorities.

acting as an appellate authority in matters of dispute relating to the quality of a drug.

collecting, storing, and distributing International Standards and International Reference Procedures for the preparation of pharmaceutical substances.

preparing of National Reference Standards and cultures used in drug analysis and also distribution of standards and cultures to State Quality Control Laboratories and drug manufacturing establishments.

training of drug analysts appointed by the State Drug Control Laboratories and other institutions.

advising the Central Drug Control Administration with respect to the quality and toxicity of unlicensed drugs.

working out analytical specifications for preparation of monographs for the Indian Pharmacopoeia and the Homeopathic Pharmacopoeia.

performing expedited analysis of lifesaving drugs.

In addition to the listed functions, the Central Drug Laboratory also actively collaborates with the World Health Organization (WHO) in the preparation of international standards and specifications for international pharmacopeias.	

Indian guidelines for research with human subjects are based on the Declaration of Helsinki, WHO, and the ICH guideline for GCP. The Indian Council of Medical Research finalized a set of ethical guidelines for biomedical research in humans in October 2000. The guidelines covered wide-ranging issues including informed consent procedures for new drug trials, fetal research, transplantation, and human genetics. One of the requirements was for institutions to obtain formal approval from a local ethics committee before commencing any clinical trial. A further requirement was for clinical trial laboratories to provide evidence of accreditation.		

Advantages of conducting clinical trials in India				

 The investigational new drug (IND) dossier in India consists of data on pharmacokinetics, preclinical studies, stability studies, published literature, copies of prescribing information from two markets, and a summary of international availability. Documentation for permission to conduct a clinical trial needs to be submitted to the DCI's office for clearance, in an application made in Form 44, under Rule 122 DA of the Drugs and Cosmetics Act 1945. The application to the licensing authority should be accompanied by a fee of Rs. 50,000 (U.S. $1020) for Phase 1 trials, Rs. 25,000 (U.S. $510) for Phase 2, and Rs. 25,000 (U.S. $510) for Phase 3.	

This dossier may be complemented by a formal presentation to the authorities by the sponsor (or appointed CRO), but a formal presentation is always required for Phase 2 and fast-tracked Phase 3 studies.	

In parallel with IND approval, the company must also obtain a test license to import the investigational product. The typical timeline for regulatory approval of a clinical trial is 12–14 weeks. Approvals for rDNA products require preapproval from the Genetic Engineering Approval Committee and may take 14–16 weeks. Applications for drugs indicated for infectious diseases can take longer.	

Articles

Feature Article

With the rapid geographical expansion of clinical trials, industry professionals are increasingly willing to set up studies in exotic locations. Although their initial concerns about the quality of data from far-flung studies have dissipated, debate continues about the ethics of performing trials in new locations, especially in developing nations.

Clinical Trials in India

Food and Drug Administration good clinical practice inspections can happen to anyone involved in conducting clinical trials in the United States. Even the most meticulous organizations experience a feeling of apprehension when faced with the prospect of having their operations, employees, and data scrutinized by federal investigators. These fears are not unfounded. If serious deficiencies are discovered, the consequences could jeopardize a study or a submission.

An FDA inspection will never be easy, but the experience will be much less traumatic when the people involved are trained to meet the requirements and pressures of the inspection process. One of the most effective ways to prepare for this challenge is by using mock inspections. By creating a learning experience that accurately simulates an inspection, an organization can test its response procedures and bolster employee knowledge and confidence to handle a real inspection more effectively.


The FDA inspection programs cover the gamut of organizations involved in the clinical trial process, including clinical investigators, sponsors and monitors, contract research organizations (CROs), laboratories, and institutional review boards. Guidelines and FDA compliance program manuals (see FDA Compliance table) detail the various types of FDA inspections. Although the rules and regulations seem complex, it helps to remember that all inspections are designed to answer a few key questions.


Is the organization knowledgeable of, and adhering to, the federal laws and regulations governing clinical trials?

Are the safety, rights, and welfare of trial subjects being protected?

Can the validity of the clinical data supporting a New Drug Application (NDA) or Biologic License Application (BLA) be confirmed?

Was the targeted study well controlled and conducted according to applicable protocols, standard operating procedures (SOPs), and regulations and guidelines?

Is complete documentation available to support all of the organization’s training, monitoring, and compliance programs?

When FDA investigators inspect a facility, they expect the organization to be able to supply timely and complete answers in support of these basic questions. Accomplishing that task quickly and efficiently, however, requires planning and practice. The time to begin preparing for FDA inspections is not the day your organization receives a Form FDA-482, Notice of Inspection. By designing and implementing a training program for FDA inspections in advance, you will better prepare your organization to meet the demands of any inspection.


Your FDA inspections training program should include several components. A good place to start is an employee training course on FDA inspections. Whether designed and taught by internal personnel or an outside instructor, the course should provide information your employees need to understand the basics of the inspection process. Topics might include:


the regulations governing inspections and the agency’s authority.

the different types of inspections, the reasons behind FDA inspections, and what the agency is looking for.

the “anatomy” of a typical inspection.

the types of information and documentation that might be required.

the people who would be involved in working with the investigators.

a review of “dos and don’ts” for the inspection.

the possible consequences of negative findings (including negative consequences for the organization).

Supporting information can be found in the FDA’s compliance program manuals (see table). The manuals spell out guidelines for inspections of various organizations and are the framework for all bioresearch-monitoring inspections.

Another important part of your preparation should be the creation of an SOP for government inspections. The SOP should cover every aspect of your organization’s actions during an inspection, such as what happens when an investigator arrives, the roles and responsibilities of each person involved in an inspection, the process(es) for retrieving and reviewing requested documents and data, actions that are permitted and not permitted during an inspection, how the inspection is documented, and the response and follow-up procedures for a Form FDA 483, Inspectional Observations. A well-designed SOP for inspections will guide your employees’ actions during the inspection and help you provide a well-organized response.

The third component of your education and training efforts should be “mock FDA inspections”-that is, conducting a simulated inspection that reflects the real experience as closely as possible. While classroom-training programs are valuable, most people who have been through an FDA inspection say that nothing quite prepared them for the intensity of the real thing. The pressure of having every aspect of your study activities and documentation scrutinized can be stressful, even intimidating, for everyone involved. In addition, although FDA investigators do not necessarily try to make the inspection process difficult, their role in maintaining the integrity of U.S. pharmaceutical products means that they take their jobs seriously.


Mock inspections are a good way for your organization to provide a training experience that approximates the intensity of a real inspection. In essence, a mock FDA inspection is a role-play that casts an individual in the role of an FDA investigator who conducts an inspection “in character” and helps the organization live through a simulated FDA inspection. This type of experience is valuable for a number of reasons. It allows you to test your “inspections SOP” under realistic conditions and to determine whether it covers the process completely and provides the guidance people need to respond to the situation quickly and appropriately.

It also gives you the opportunity to analyze your logistic capabilities, corporate procedures, and information systems to determine whether they can handle the documentation and data demands of an inspection in a timely fashion. As a result, you can identify and correct weaknesses and can enhance your systems and procedures before their shortcomings inflict damage on your organization.

Another important benefit of mock inspections is their ability to make the inspection process more real to those who have never participated in one. With the experience of mock inspections, your employees will have a much better idea about the types of questions they might be asked, what role they should play, and how they should react in various situations. They will also have a greater appreciation of the seriousness of the inspection process and its importance to your organization. With that combination of knowledge and practice, there is a much greater likelihood that they will respond properly and handle their roles professionally during an actual inspection. Participation in mock inspections should also reduce the anxiety level of those who are later involved in real inspections. It should be noted that a successful inspection depends primarily on good quality data and having knowledgeable people available to present the data to the FDA.

Realistic role-playing is vital if you are to realize these and other benefits of your mock inspection program. This is especially true in the case of the person playing the role of the FDA investigator. By remaining “in character” throughout the mock inspection, the instructor sets an important example for the rest of those involved to act as if the inspection is real, which greatly enhances the education value of the exercise. The person you select to be the mock investigator should have experience with FDA inspections, as well as an in-depth understanding of the relevant FDA guidelines. If you are selecting from your internal resources, this would usually be someone in your quality assurance (QA) group. You should also look for an individual who will be enthusiastic about the role-playing aspect of this assignment.

Executive-level management support is another essential ingredient for the success of a mock inspection program. Because these exercises require a substantial investment of time and effort above and beyond your employees’ regular duties-and a certain amount of disruption at the inspection site-senior managers must make it clear that they strongly support the program and must encourage employees to invest the energy and dedication necessary for it to succeed. Executive support can be demonstrated through personal participation in the mock inspection and by allocating funds for the educational effort, as well as by giving the participants the flexibility to participate fully.


Once your educational programs and SOPs are in place, you will need to select studies to subject to the mock inspection. The selection criteria used by the FDA are good guides. A typical choice would be a recently completed pivotal Phase 3 study that included a significant number of subjects. Also consider the accessibility of study data and the personnel who would be involved if a particular study were selected. The goal is to choose studies that fairly represent the type of work your organization does and that also will provide an accurate test of your people and infrastructure.

After you select a specific location and study, develop a plan for your mock inspection, based on your SOP and the appropriate FDA compliance program manual. The plan should clearly state the objectives of the inspection, the project and location selected, the people who will participate, and time frames for completing the inspection. Pay special attention to developing the requests for information that your mock inspector will issue, keeping in mind the key questions about regulatory knowledge, data validation, adherence to SOPs, and documentation of compliance. Most important, incorporate an educational program into the mock inspection process. Decide how and when the participants will be “debriefed,” and how you will follow up on the lessons learned from the exercise.

When you actually conduct the mock inspection, try to make it as real as possible. Follow your plan, and treat the mock FDA investigator exactly as you would treat the real investigator during an actual inspection-from the time he or she walks into the building until the inspection is completed. Everyone should try to stay in character throughout the process to maximize the learning experience.

Inviting managers, executives, and people from other projects to sit in on the mock inspection is also useful. They can observe the inspection as part of the educational process.


Because the mock inspection is an educational exercise, an immediate and thorough review of the lessons learned is absolutely vital following the inspection. This review can occur at the end of each day of the mock inspection, or at its conclusion, but doing the review while the details are still fresh is essential. This review process should include:


comments from the person playing the FDA investigator about what was done well and where improvement is needed.

observations from the QA team and others who observed the proceedings.

input from the participants, both on what happened during the inspection, and on the value of the exercise itself.

the creation of an action plan about how to address the compliance concerns and organizational shortcomings revealed during the mock inspection.

a follow-up report to ensure that the action plan is being implemented.

During the debriefing process, your team should address any negative feelings that may have resulted from the mock inspection. Even though it’s just a training exercise, a realistic mock inspection can sometimes upset people or leave them feeling that they were unfairly singled out or criticized. Some may also be concerned that any problems uncovered during the mock inspection will somehow be held against them. The executives and managers involved in the exercise should make a special effort to reassure the participants that the results will not create repercussions in their job. Without this assurance, the value of future mock inspections could be compromised by employee reticence.

Because such mock inspections should be an ongoing part of any clinical organization’s training program, management support and employee participation in the program is vital. By holding these exercises periodically, more people can share the learning experience, and the organization can continually improve its level of preparedness for real inspections, as well as improve its operational systems.

Mock inspections can effectively test the preparedness of a site or sponsor-and also train employees to handle a real FDA inspection.

Using Mock Inspections to Prepare for FDA GCP Inspections

The casuists of the Counter-Reformation would have found delight in the European Union debates on clinical trials. The debates offer an intricacy that could feed the appetite of the most avid sophist. But its hard work for the 21st-century clinical trial practitioner to keep abreast of the latest twists in the elaborate rococo design of the EU rules that governor will governhis or her work.

The latest twist comes not from the clinical trials directive itselfstill awaiting full implementation (View from Brussels, 

, November 2002)but from the wider debate on the review of all the EUs pharmaceutical rules.

 In early 2001 the EU proposed changes to the basic EU rules on medicines authorization, nominally to speed up and improve authorization decisions, to ensure a high level of public health protection, and to simplify the system. These proposals have been debated at length by the 15 EU member states and by the European Parliament, which delivered its first opinion on the proposals in November 2002. A decision, however, is still monthseven yearsaway.

 The EU has modified its draft text for the regulation at the heart of the proposals, its 2001 draft regulation of the European Parliament and of the council laying down community procedures for authorization, supervision, and pharmacovigilance of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products. (The new text is available at: europa.eu.int/ eur-lex/en/com/pdf/2002/com2002_0735en01.pdf.) The changes take account of many of the multiple views expressed by the European Parliament, and a new debate will start on that basis. Some changes have direct relevance to clinical trials; many have indirect relevance; and the package as a whole remains a crucial influence on the future shape of European pharmaceutical regulationhowever it finally turns out.


The new text, drawn up by the European Commission (which is responsible for making legislative proposals in the EU), reflects acceptance of the principle in one of Parliaments amendments relating to the application of the ethical requirements of Directive 2001/20/EC on the implementation of good clinical practice in the conduct of clinical trials on medicines authorized by the EU, and to clinical trials conducted outside the EU on products destined to be authorized by the EU. The new wording reads: 


There is also a need to provide for the ethical requirements of Directive 2001/20/EC of the European Parliament and the Council 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 (footnote: Official Journal of the European Communities L 121 of 1.5.2001, p. 34) to apply to medicinal products authorized by the Community. In particular, with respect to clinical trials conducted outside the Community on medicinal products destined to be authorized within the Community, at the time of the evaluation of the application for authorization, it will be verified that these trials were conducted respecting the principles of good clinical practice and the ethical requirements equivalent to the provisions of this Directive.

In some areas, the Commission has accepted the principle of European Parliament amendments, but has not considered changing its proposal accordingly because EU rules already cater to such needs. For instance, an amendment aimed at boosting clinical trials in children is not necessary because the clinical trials directive already contains specific provisions that apply to studies conducted in children. Similarly, the Commission also accepted the principle of another amendment aimed at providing that the new database on medicinal products, which is to be established by the European Commission under the proposals, contains information relating to clinical trials. But in this case too, the Commission says there is no need for any change to its proposal: the addition of such a provision does not appear to be necessary; the Directive on clinical trials already provides for a specific database for clinical trials conducted with a view to the authorization of medicinal products for human use.

Some European Parliament amendments have been turned down flat by the Commission because they cover areas already dealt with or to be dealt with in legislation currently in the pipeline. For instance, the Commission says new obligations are not needed concerning pediatric indications or for a provision obliging the scientific committee to consult experts in pediatrics. The issues concerning medicinal products for pediatric use will be taken up in the future legislative proposal that will be aimed specifically at the questions relating to these medicinal products, it says. Parliament requests to include data concerning pharmaco-vigilance in the database on authorized medicinal products are also excessive, says the Commission.

The new text also introduces some elements that will speed up processing of applications. For clarity, the Commission has changed the wording of provisions concerning the authorization of certain medicines under exceptional circumstances, as follows:


In exceptional circumstances and following consultation with the applicant, authorization may be granted subject to a requirement to introduce specific procedures, in particular concerning the safety of the medicinal product, for notifying the relevant authorities of any incident related to its use and for any action taken. This authorization may be granted only for objective, verifiable reasons and must be based on one of the grounds set out in annex I to Directive 2001/83/EC. The maintenance of the authorization is bound to the annual reassessment of these requirements.

The Commission has accepted the principle of amendments aimed at permitting the European Agency for the Evaluation of Medicinal Products to recommend conditions relating to the use of certain medicinal products so as to guarantee their safe and effective use. A new point is added to the effect that EMEA committee opinions may contain details of any conditions or restrictions which should be imposed so as to guarantee the safe and effective use of the medicinal product, in particular mechanisms for controlling and monitoring its use and administration.

Likewise, the Commission has endorsed the principle of an accelerated procedure for medicinal products used in certain treatments with a view to making them available to patients more quicklybut has pointed out that this procedure is already foreseen in the initial draft text, and an additional reference is, therefore, not necessary.


The Commission has played a rather cautious hand on some areasnotably on comparative efficacy, which the Parliament called for a reference to, and which many EU member states already use in their national decisions on pricing and reimbursement of medicines. It is important to emphasize that this evaluation should not be considered as a necessary criterion for the application or for the authorization of medicinal products. In effect only the criteria of the quality, safety, and efficacy of the particular medicinal product should be used in the evaluation of medicinal products, explains the Commission. So it is proposing wording as follows:


The Member States have developed an evaluation of the comparative efficacy of medicinal products aimed at positioning a new medicinal product with respect to those that already exist in the same therapeutic class. Similarly, the Council, in its conclusions on medicinal products and public health, adopted on 29 June 2000, emphasized the importance of identifying medicinal products that presented an added therapeutic value. However this evaluation should not be conducted in the context of the marketing authorization for which it is agreed that the fundamental criteria should be retained. It is useful in this respect to allow for the possibility to gather information on the methods used by the Member States to determine the therapeutic benefit obtained by each new medicinal product.

A new article is also introduced to provide for the possibility for the EMEA, at the request of the Commission, to collect information from the competent authorities of the member states in charge of performing evaluations of efficacy compared to that of already authorized medicinal products, worded as follows: At the request of the Commission, the Agency will collect information on the methods used by the competent authorities in the Member States to determine the therapeutic progress contributed by each new medicinal product.

A number of changes have been introduced relating to pharmacovigilance. To provide public funding for the EMEA commensurate with its pharmacovigilance activities, the Commission has reworded its text as follows: In order to ensure full independence, the activities relating to pharmacovigilance, to the operation of communications networks and to market surveillance should receive guaranteed and adequate funding. To allow a role for patients in the communication of adverse effects, it proposes new wording.


to limit the number receiving these communications; in effect it does not seem appropriate that patients should transmit this information directly to marketing authorization holders, without the intervention of a health-care professional or a competent authority who could manage or filter such information.

The holder of the marketing authorization and the competent authorities of the Member States shall ensure that all relevant information about suspected adverse reactions to the medicinal products for human use authorized under this Regulation are brought to the attention of the Agency in accordance with the provisions of this Regulation. Patients shall be encouraged to communicate any adverse reaction to their health-care professionals or to the competent authorities for pharmacovigilance.

To clarify the timelines for the submission of the first updated period in safety report and the contents of these reports, it proposes rewording of its initial draft text as follows.
Unless other requirements have been laid down as a condition of granting of the marketing authorization by the Community, these records shall be submitted in the form of an updated periodical report on safety, to the Agency and Member States immediately upon request or at least every six months during the first two years following the initial placing on the market in the Community, and once a year for the following two years. Thereafter, the reports shall be submitted at three-yearly intervals, or immediately on request. These reports shall be accompanied by a scientific evaluation, notably a benefit-risk analysis of the medicinal product.

To clarify the contents of the guidance to be developed for the collection, verification, and presentation of adverse reaction reports, the Commission rewords its text.

The Commission, in consultation with the Agency, the Member States and interested parties, shall draw up guidance on the collection, verification and presentation of adverse reaction reports. This guidance shall contain, in particular for the benefit of health-care professionals, rules concerning the transmission of information on adverse reactions.


Some of the changes could make conditions tighter for companies marketing their products. They would allow, for instance, for withdrawal of products if the envisaged tighter postmarketing shows they have a negative benefit/risk analysis. And companies would not be allowed to communicate any information concerning postmarketing data on their products to the general public without the consent of the EMEA.

Other changes the Commission has made could also permit faster processing of authorization applicationscutting to just 15 days the delay for the European Agency for the Evaluation of Medicinal Products to send draft decisions on authorizations to the member states, and for the Commission (which is legally responsible for the final decision) to act. The Commission has also agreed to provide public access to information about all refusals, and the reasons for them. And while it retains its plan to annul the authorization of a product that has not been marketed within three years, it will now allow companies to challenge such decisions in exceptional circumstances and on public health grounds.


This is still barely the halfway stage in the process. Alongside the draft regulation, a draft directive is also under discussion. The Councils Common Position is not expected early in the new year. And once that emerges, the proposals will then, of course, go back to the European Parliament for second reading. As the European Federation of Pharmaceutical Industries and Associations is warning, it could be 2004 before the new rules are agreed upon.            

View from Brussels

The latest wrinkle in the European Union?s clinical trials rules debate comes from modifications of the draft text at the core of its proposal.

Tweaking the EU Rules on Clinical Trials

The campaign to combat the AIDS epidemic and other major diseases prevalent in developing nations is spurring development of a global clinical research infrastructure and focusing attention on international research policies and practices. These developments have been praised and debated at numerous international conferences during the past year that aim to spur investment in developing new vaccines and medicines to treat AIDS, malaria, and tuberculosis.

According to a recent report from PhRMA (Pharmaceutical Research and Manufacturers of America), sponsors are testing 83 new AIDS medicines, including 14 vaccine candidates, with one in Phase 3 clinical trials in Thailand and other countries. International health experts and patient advocates, however, insist that much more needs to be done.

Delegates at the World AIDS Conference in Barcelona in July 2002 heard reports from scientists on progressand disappointmentin developing new vaccines and therapies. While participants booed Health and Human Services secretary Tommy Thompson for failing to provide more funds to global anti-AIDS efforts, the gathering also reflected continued tension between those medical and patient groups that want more funds to treat the millions already infected by AIDS, and organizations that want to invest primarily in prevention and vaccine research.

Further discussion of these issues took place at the World Summit on Sustainable Development in Johannesburg in September, where Secretary of State Colin Powell similarly drew criticism for the Bush administrations inadequate funding of disease treatment in Africa. World AIDS Day in December prompted additional pledges from major nations to increase support for international disease prevention and treatment programs.


This growing support for global disease research is enabling donor organizations and health foundations to invest more in research programs and in establishing international clinical trial networks to test promising therapies. A major roadblock to developing new medicines to combat diseases in developing countries is the lack of clinical research capability in those countries, according to a report on the State of the Worlds Vaccines and Immunization from the World Health Organization (WHO), UNICEF, and the World Bank.

 The report points out that progress on vaccines for developing nations is stalled because of a limited number of research centers with the capacity and experience needed to conduct large-scale vaccine trials in poorer nations. It urges additional support for public-private partnerships to support clinical studies in developing nations, as is being done by the Malaria Vaccine Initiative (MVI) and the International AIDS Vaccines Initiative (IAVI).

Parallel clinical trials in industrial nations and developing countries are essential, the WHO report notes, to evaluate key differences in how vaccines affect differing populations. Vaccines often have to treat variations in the serotype or strain of a disease-causing organism, and population differences may affect dosage regimens. Clinical studies in developing nations should be carried out at an early stage in a drug development program to establish accurate forecasts of demand and to avoid gaps between when a new vaccine is available in wealthy and poor nations.

Overcoming obstaclesOpportunities and roadblocks to research in developing nations were discussed at the Partnering for Global Health Forum 2002 sponsored by the Biotechnology Industry Organization (BIO) and the Bill & Melinda Gates Foundation in Washington, D.C., in December. The forum brought together public- and private-sector funding organizations, such as the Gates Foundation and groups associated with the World Bank and the United Nations, with biotech companies seeking support for research and development programs that address AIDS and other diseases prevalent in developing nations.

Presentations described a host of initiatives for conducting research and for improving local clinical trial infrastructures.

The Global Alliance for TB Drug Development

 is forming an international clinical trial site network to test promising therapies. The aim is to provide support for a range of compounds and treatments to broaden chances for success.

 is creating AIDS Vaccine Development Partnerships (VDPs) with pharma companies, biotech firms, and contract organizations that provide overall management and coordination of multiple research programs. IAVI is now building a regulatory team, in addition to its clinical team, to help small companies navigate the regulatory and oversight process. It also has established core laboratories that meet global quality standards to provide test data. 

 based in Ghana, has field sites in 16 countries in Africa and Asia. The network (www.indepth-network.net) monitors almost two million people, providing a platform for evaluating a wide range of health-care innovations and for conducting multisite research studies, particularly for testing vaccines and drugs for AIDS, tuberculosis, and malaria. The organization is training study monitors and investigators, improving local health facilities, and establishing ethics committees. 


The INDEPTH network is one sign of considerable improvement in clinical trial operations in Africa over the last 30 years, observed Brian Greenwood of the London School of Hygiene and Tropical Medicine. Speaking at the forum, he noted that multiple ethics committees and viable consent procedures now exist, and that the number of trained investigators has increased noticeably. Logistics and transportation remain major problems, however. Solar power development is important for facilitating vaccine refrigeration and mobile phone communications, which greatly improves clinical data management.

Sponsors acknowledge the need to provide medical care to clinical trial participants, but the debate continues over whether that care has to meet standards of Washington, D.C., or London, or adhere to local conditions. An even trickier issue is what kind of continuing medical care a sponsor should provide to trial participants after a study is over. The pharmaceutical industry cannot use developing countries as a testing ground for products for the industrial world, Greenwood commented. But who does have long-term responsibility for caring for large patient populations (see sidebar) is unclear.


As programs to develop new vaccines and therapies show promise, health experts and funding organizations also are recognizing the need to plan for global manufacturing of any new treatments. Large-scale production is needed to provide vaccines for Phase 3 trials, which can involve thousands of participants. And to be able to produce a vaccine as soon as it is licensed, plant construction has to begin before sponsors have assurance that a test product will work. Construction of a vaccine manufacturing plant that meets GMP (good manufacturing practices) standards often requires several years and at least $50 million, but the numbers can be much higher for an AIDS vaccine that would be needed by much of the world.

IAVI is devoting considerable resources to formulating a plan for massive AIDS vaccine production. The nonprofit organization aims to link academic research efforts with networks able to conduct clinical trials in developing nations and with the product development skills found in the vaccine industry. To speed vaccines to Phase 1 trials, IAVI uses contract manufacturers to produce pilot lots for preclinical testing and for early clinical studies. Now it is beginning to map plans for constructing vaccine facilities able to supply millions of vaccine doses for developing nations.


While clinical research and other initiatives move forward, industry and health policy experts are examining economic and political factors likely to spur or discourage research and development of new vaccines and other treatments for global diseases. These include push approaches such as tax breaks and research grants that provide incentives for private sector investment in research. In addition, experts are increasing their focus on pull strategies that involve guaranteeing markets and future prices to promote private sector investment.

The Global Alliance for Vaccines and Immunization (GAVI) is promoting accelerated development and introduction plans (ADIPs) to help countries establish credible vaccine demand forecasts that are key to securing long-term financing for vaccine programs. The aim is to develop these forecasts early in the vaccine development cycle, before manufacturers undertake scale-up to encourage construction of production facilities sufficient to meet future demand.

WHO is helping to strengthen national regulatory authorities by assisting them in developing clear requirements for product licensing, field surveillance programs, lot release systems, laboratory testing capabilities, and regular manufacturer inspection programs to ensure compliance with GMPs.

Patient advocates and developing countries continue to complain that industrial nations are not providing enough support for the campaign against AIDS and other diseases prevalent in developing nations. Last fall, Congressional committees expanded funding for international AIDS programs in foreign aid funding bills for 2003, but were unable to reach final agreement on the budget plan. The Bush administration recently unveiled a new foreign aid plan that could expand the pool of funds available to support treatment and research for AIDS and other diseases. Political leaders in the United States and other countries increasingly recognize that the high economic and political costs imposed by the AIDS epidemic create a serious threat to stability and growth in Africa and other parts of the world.


1. www.unicef.org/noteworthy/sowvi/ sowv_en_2002_rev.pdf.

SIDEBAR: Promoting fair benefits for research populations


To avoid exploiting inhabitants of a poor country who agree to participate in a research program, current policy calls for sponsors to make safe and effective products developed through local testing reasonably available to those involved in a study. Defining how to meet such commitments has been very difficult and has raised questions about what standard of care sponsors should provide to study participants and broader patient populations in developing countries.

To address the issue, participants in a conference on Ethical Aspects of Research in Developing Countries, which was held in Malawi in March 2001, developed a new approach for dealing with these complex issues.

 They offer the populations of developing nations a new framework for providing fair benefits, which include:


 benefits to study participants during research, such as health care and collateral health services.

 benefits to a broader population while research is going on, such as additional health services, improvements in public health programs, and employment and economic activity generated by the study.

 benefits to a population after the research has been conducted. This may include access to an effective intervention, improvements in local medical care and public health, future opportunities for research collaboration, and possible financial gains from research results.

In determining what constitutes fair benefits, the framework calls for researchers to form a collaborative partnership with the local population in developing and evaluating a research program. And it emphasizes the need for transparency and local consultation in defining agreements and policies. An entire region or country may not share equally in the distribution of benefits or in making decisions on the program, and the policy emphasizes fairness over equality in assessing benefits or possible exploitation.


1. Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries, ETHICS: Fair Benefits for Research in Developing Countries, 

 298: 2133 (2002); also available from www.sciencemag.org/cgi/content/full/298/5601/2133.            

View from Washington

Sponsors tackle international research challenges to develop AIDS, malaria, and TB therapies for developing nations.

AIDS Campaign Spotlights Global Clinical Research

When railroads were first being laid across the country, the woodsmen who felled the trees to make way for the tracks were heroes. A tale was told of one particular woodsman of Bunyanesque achievements who mowed down trees at a terrific rate. After some weeks of this furious effort, news filtered back to the crew chief that the heroic woodsman had slowed down considerably. Worried, the crew chief rode out on his horse to find the logger. He discovered the man (lets call him Paul), on his knees, shirt off, sweat flying, flailing away at a particularly large tree trunkmaking no headway at all. The boss asked Paul to stop for a moment and show him his axe. When the boss felt the edge of the blade, it was as dull as a butter knife. Paul, the boss said. No wonder youre exhausted and getting nowhere. Youve got to stop and sharpen this blade. Paul looked at the trees that stood in the path before him and scoffed, I cant stop, I have too much work to do!

The lesson to be learned from this tale is one sorely needed by clinical research departments all across our industry. Be it in clinical monitoring, medical affairs, data management, or wherever processes need improvement, the universal cry is, I cant stop, I have too much work to do!

The examples are plentiful. We urgently push ahead with dull-bladed processes for protocol approval, edit check development, investigator evaluation, subject recruitment, site monitoring visits, adverse event tracking, data queries, subject-generated diaries, investigator payments, project management, and program decision making. We push ahead, knowing we could do better, knowing we need to stop and sharpen the blade, knowing we are falling farther behind. We get caught in the fallacy that we are too busyor cannot afford to allocate the fundingto stop and do it better. How can we? We have trials to do!


Lets look at some real-life examples. The circumstances have been changed a bit to protect the guilty. A small biopharmaceutical company has a lead compound in an esoteric therapeutic area, and its pivotal Phase 3 trial will require a large number of hard-to-find subjects. Subject recruitment companies submit various proposals to meet the challenge, all of which are very expensive and use timelines that are much too long. The clinical director suggests using well-informed colleagues outside the company to call every known possible site and prequalify them for subject eligibility. The clinical directors colleagues say they can do it in less than a month. The vice president rejects the idea because it would cost too much, and tells the already overworked clinical director to make the calls herself, which to him means, It wont cost anything to do it ourselves.

The result? It takes the companys own clinical staff months to reach about half the sites, and the information they get is not encouraging. Meanwhile, the trial is already underwayin order to keep the trials going and to satisfy investorsand recruitment is poor. In addition, the clinical director has been fatally distracted from her many other duties critical to the companys broader program.

If the company had instead spent the money up front on the 30-day calling program, the management team would have found out before having to start the trial that prospects for recruitment were dismal and another study design should be found. Obviously, starting up the study without sufficient information on available subjects was many times more expensive than what the calling project would have been. Penny-wise, pound-foolish, or as we say, I cant afford to save money.

We can cite many other examples that will be familiar to the reader. Companies that spend millions on new software applications, without paying what may amount to less than 20% of the purchase price to implement a project for properly changing the work processes to fit the new software. Or changing the process of data cleaning (say, backing off from 100% source data verification) but not paying for training the monitors in the why and how. Or buying generic SOPs that end up being thrown away, or which need so much revision it would have been cheaper to have someone write new ones from scratch. And so on.


Lets look at another example. A clinical operations department has ample evidence that its processes are confused and inefficient. Regional monitors report that different home office project managers manage their projects differently. Relations with clinical data management are strained. In-house clinical research associates (CRAs) are complaining about the field CRAs, and vice versa. Roles and responsibilities have become fragmented and inconsistent. Realizing her department is a mess, the clinical operations director calls in a consultant to discuss remedies. The solutions sound great to her. But sorry, she says. We dont have time for them. The director goes on: I can only yank the regional monitors out of the field once a year (theyre too busy otherwise), so I can give you two hours on Tuesday at the annual meeting. Is that enough time?

What about the process mapping exercise for the home office departments to figure out how to work better together? the consultant asks.

 Oh no, that takes up way too much time, and we couldnt possibly get everybodys schedules to line up together.

It took a hundred people and 10 years to make their operational process work this badly. Can we seriously expect that two hours on Tuesday will fix it? They know they have the problem, but they dont have the time to stop and sharpen the blade. Or as we say, I dont have time to save time.

Stories like these can be found in every company. It is always difficult to interrupt everyday work, work that is critical and overextended, and ask people to essentially work on something elseto work on making things better. It may seem impossible to do what we know is rightto try and save time and money by spending time and money. Without doing so, we end up like Paul the woodsman, down on our knees, flailing away at a massive tree trunk with our dull-edged axe. The ease with which your tasks proceed as you wield a finely honed axe will more than make up for the time and money you spent on sharpening the blade.            

Process Improvement

It may seem impossible to do what we know is right?to try to save time and money by spending time and money.

The Woodsman?s Tale

Clinical trials are a vital step toward bringing new drugs to market. U.S.-based clinical trial activities increased by 6% in 2001, the largest rise since 1990.

 But although pharmaceutical companies pay close attention to the science when designing their clinical trials, few consider how they will get enough subjects to participate. As a result, most trials are plagued by delays that can cost pharmaceutical companies millions of missed sales. Delays in getting a drug to market are estimated to cost companies around $1 million a day.

To minimize time to market, sponsors must explore new subject recruitment techniques.

New Ways to Recruit Trial Subjects

Choosing the optimal study design in a drug development plan requires a high level of experience in the relevant indications, the medical environment, and regulatory requirements. It is also vital for the researchers ethical responsibility and the commercial success of a drug. But expertise in project and logistics management is just as important to the success of a clinical trialand it is often taken for granted. Multicenter trials, and those that are also multinational, especially require extensive planning and management.

Planning is a process that requires management. The reason that most projects fail to meet their timelines is that planning is not managed thoroughly enough. The planning process deserves attention and monitoring in parallel with the other components of clinical research.

Once the need and objectives for a trial are defined, proper planning over a period of at least six months is vital to ensure a successful study management. Planning should equally emphasize ideal scenarios, contingency plans, and risk management at all key steps in the form of what if analyses.Decisions on consequences and solutions for different potential outcomes should be planned up front, not made at the last minute or in crisis situations.

Although perceived as minutious and cumbersome, planning can be organized and structured in a clear, simplified mode. Planning can also be understood as an investment with quantified and specific returns.

The following approach can help optimize the preparation of a multinational multicenter trial. For each month leading up to the enrollment of the first subject, we suggest the key activities outlined in the accompanying checklist for day-to-day use of 100 Points to Consider for Effective Study Preparation.


Study planning is only one component of an overall successful drug development plan. Whenever possible, key elements of the respective study designs should preexist and be kept current in a master development plan.

Not all elements can be or need to be finalized at that time, but they all need to be under control for content and timelines, with assigned accountabilities within the core project team.

Thorough evaluation of expert opinions, current literature, and the availability of sufficient pharmacology, toxicology, and clinical data help to achieve consensus among all relevant parties involved regarding study objective, rationale, and scientific methodology. This should include evaluation of expert opinions; current literature; and availability of sufficient pharmacology, toxicology, and clinical data.

Completing this first step should in turn trigger operational planning timelines for targeted final evaluations; availability of study drugs, comparators, and placebo; and selection of countries of interest for study execution.

To prevent delays and cost increases at later stages, the following key risks need to be assessed and options for solutions need to be worked out:


	Document management (that is, need for investigator brochure and/or local regulatorydocumentation)

	Detailed project plan with key event dates

	Selection of technologies to be used (for example, IVRS, remote data entry, e-CRF)

	Functional resource planning with geographical deployment.


Although design and strategies are essential, the success of a clinical trial depends on the ability to plan. This includes validation of availability of subjects, and also availability of investigators and study management resources (for example, vendors and geographic deployment of internal resources).

The project team should be identified for all core functions involved.

Key aspects of drug supply management such as labeling and importation requirements, manufacturing, and packaging and distribution plans should be defined and initiated at this stage.

	a back-up strategy for countries and site selection.

	a contingency plan for packaging and shipment delays.

	subject recruitment initiatives, as legally possible. 

	user requirements for vendor management (insourcing and outsourcing).


This plan proposal assumes that generic toolsmaster agreements and contract templatesare already in place for core standard terms for vendors, investigators, and grant management. It is further assumed that a contract research organization (CRO) is not intended to participate in the early study planning phase.

Based on the results of the feasibility study, sites should be selected, the study discussed with investigators, and the terms and conditions negotiated with prequalified sites. A series of operational documents should be prepared: operational sections of protocol, standard informed consent, case report form (CRF), updated investigator brochure, and information and advertisement materials.

An investigator meeting(s) and all related aspects should also be prepared. The importance of a well-thought-through overall communication plan, which defines in detail the structure of the project team, including vendors, and the lines and ways of communication within the project team and with investigators, ethics committees, and regulatory authorities, is often overlooked and should be designed and deployed. This communication plan is critical to success.

At this stage, vendor management should be proceeding well, the budgetary options are ready in case recruitment issues arise, and local standards should be known and in place for study initiation.


Local readiness now needs to be achieved, including:


	submission to local independent ethics committees and health authorities.

	assessment of drug labeling and importation requirements.

	collection of appropriate essential documents from investigational sites.

	definition of process flow for safety handling and all other identified needs (for example, specific personnel and budget needs).

	selection of sites confirmed by prestudy visits.

In parallel, specific plans for data management and quality assurance need to be prepared.At this time in the planning process, resources must be reliably assigned in all operational locations, ensuring a timely study start as well as continuous and updated knowledge of local requirements. Ideally, letters of intent with vendors should be agreed upon.


Monitoring and data management conventions should be checked for consistency and integrated into training packages and the statistical plan.

The CRF design should be finalized and action taken to work out printing order and logistics for shipment.

Database design, including safety rules, should be put in place and validated.

A quality control check of processes, procedures, and resources should now be conducted so that alterations or corrections can be made before the study starts.

1 month ahead: Training and site management


The project team, vendors, investigators, and study site personnel need an extensive introduction to,  and training in, the study details. Suitable tools for accomplishing that include investigators meetings with all parties involved, study initiation visits, project team kickoff meetings, and the use of media tools as appropriate.

After a final check of the availability of all required study prerequisites, subject recruitment can start.


Although everyone seems able to find the time and money to redo, finding the time and budget to plan properly seems very rare. Planning, however, is a key function, not just an intuitive process that scientific professionals can handle spontaneously.

What happens in the six months before a trial is just as important as what happens during the trial.