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Feature Article

An essential aspect of selecting the location for an investigative site is the population surrounding it. Here is a method for determining how many potential subjects are available to your investigators.

Consider Geography When Choosing Investigative Sites

Meet the EAB

Through open discussion and dialogue, and by promoting understanding and trust, Crawley?a longtime member of the European Forum for Good Clinical Practice?champions ethical research.

Meet the Editorial Advisory Board Francis Crawley

9th ACT European Summit

The system is an important part of the selection equation in CEE nations where sponsors must contract with institutions rather than investigators. Examples from Hungary offer guidelines for improving selection SOPs.

Selecting Sites and Investigators


The purpose in contacting you is to raise a query regarding a news item published in the January 2002 issue of 

. I wonder whether you could shed some light on itor am I just plain wrong!

CenterWatch Study Qualifies Risk to Clinical Trial Participants (

, January 2002, p. 19) describes the occurrence of 13 deaths attributable to study drug effects amongst 122,000 subjects participating in trials for 130 randomly selected NDAs that had received approval since 1987. It concludes that the incidence of death attributable to investigational treatment is rare.

This seems to me to be anything but rare. These figures, if true, work out at one death for every 9,385 subjects involved in clinical trials! It may be even more alarming when one considers that a proportion of the investigational treatments may have been placebo if the trial was of an inactive comparator crossover design.  

I have not seen the metrics published by CenterWatch, and so have not been able to pursue my concerns further. Perhaps you may be able to help me.

 FRQA
Crossland Consultancy
Swettenham Village, Cheshire, UK



Thank you, Nigel, for your feedback. To clarify our findings, CenterWatch analyzed a subset of approved drugs between 1987 and 2001. In all, 126 approved drugs were evaluatedrepresenting nearly one-third of all new molecular entities approved by the FDA since 1987.

We found that each year, on average, 17,200 adverse events (AEs) and 800 serious adverse events (SAEs) are reported to the FDA for approved drugs. Each year, an average of 3.6 deaths attributed to study drug effects are reported to the FDA for approved drugs. This result compares to 0.8 deaths reported to the Office for Human Research Protections (OHRP) for government-funded clinical trials.

We also found that an average of one adverse event per study subject is reported to the FDA, and an average of one out of 30 study subjects on a study drug will have a serious adverse event. Lastly, we found that in reports from industry to the FDA, one out of 10,000 study subjects have died as a result of study drug effects while participating in clinical research studies. 

To put this latter statistic into perspective, based on sponsor reports to FDA, more people die from motor vehicle accidents each year than from participating in a clinical trial. The risk of death to a study subject is nearly equal to that of a woman dying during childbirth. Many ethicists and industry professionals consider this an acceptable level of risk relative to the benefits that certain investigational treatments offer.

Our findings articulate the general risks but the data are averages, so they do not convey the high level of variability between clinical studies. Numerous variables affect research risk, including indication area, type of drug, and study duration. Severe, life-threatening illnesses tend to have a higher incidence of adverse reactions and deaths. Studies that are longer in duration tend to report higher levels of adverse events. Sponsors also subjectively define an adverse event. Whereas one sponsor may view a group of related symptoms (fever, cough, and runny nose, for example) as a single AE, another sponsor may require that the site count each symptom as a separate AE.

Our analysis is also based on FDA data from approved NDAs. We have not yet evaluated the many industry-sponsored trials that are terminated before an NDA is filed. As a result, our findings are evolving and we hope to publish revised estimates shortly.To receive a copy of the full article, Quantifying Risk in Clinical Trials, and a detailed description of the methodology, please send me an email at kenneth.getz@centerwatch.com.


President and Publisher
CenterWatch
Boston, MA


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Readers respond to articles and editorials.

Risk management is in the spotlight at the Food and Drug Administration as the agency seeks to gain more control over the way therapies are used in medical practice. The agency is reorganizing its staff and developing new policies to improve processes for evaluating risk factors in new drug candidates and to improve processes for tracking and evaluating adverse events once a product is on the market. These developments are generating calls from some experts for longer and larger studies to capture adequate safety information and are prompting sponsors to consider risk management in product development programs.

In recent months, FDA has taken action to enhance its ability to manage postmarketing safety issues. The most visible initiative involves establishing a new Office of Pharmacoepidemiology and Statistical Science (OPSS) in the Center for Drug Evaluation and Research (CDER). The main component of this new super office is the renamed Office of Drug Safety (ODS; formerly the Office of Post-Marketing Drug Risk Assessment, or OPDRA). Both OPDRA and CDERs Office of Biostatistics were shifted to OPSS from CDERs Office of Review Management.

Related to these changes, ORM was renamed the Office of New Drugs (OND) to reflect its increased focus on the review and approval of new drug applications and supplements. That office will work closely with the new drug safety office to evaluate risk concerns during the review process. OND is headed by John Jenkins, who was selected as director in December. CDER is developing internal policies for such issues as tradename reviews, post-marketing safety issues, evaluation of risk management programs, and medication guides to coordinate activities by the review divisions and ODS. ODS now manages its expanded functions through three divisions.

 Julie Beitz heads a group of more than 40 people who work with CDER medical reviewers to identify and evaluate the context of safety reports as part of the new drug review process. The group prepares materials for FDA advisory committees and participates in CDER preapproval safety conferences. The staff includes 10 epidemiologists to review protocols for Phase 4 studies and to advise on postapproval risk management strategies, such as patient registries and restricted distribution programs. After the approval of a new drug, the staff reviews adverse event reports to detect and assess safety signals and evaluates patient databases and published literature to estimate the public health impact of risk issues. 

Medication Errors and Technical Support (METS).

 Jerry Phillips is acting director of METS, and also serves as ODS associate director. The METS staff analyzes medication errors involving marketed drugs and reviews all proprietary names and labeling prior to approval to reduce the potential for confusion that can lead to medication errors.Surveillance, Research, and Communication Support (SRCS). Under Anne Trontell, this new unit will handle data resources, risk communication, and outcomes research related to drug safety risk management programs. It assumes management of FDAs MedWatch program, previously run out of a CDER staff office, and activities formerly handled by CDERs Division of Drug Marketing, Advertising, and Communications (DDMAC). These include development of Med Guides, patient package inserts, and pharmacy information surveys. SRCS provides international regulatory liaison for postmarketing safety issues and manages FDA use of drug safety and epidemiologic data resources, including CDERs Adverse Event Reporting System (AERS), drug-use data from IMS Health, and access to insurance and health plan databases. 


Heading up OPSS is Paul Seligman, who came to FDA from the Department of Energy in July. Seligman was deputy assistant secretary for health studies at DOE, where he was involved with epidemiology and surveillance programs related to radiology and nuclear weapons. He reports to CDER deputy director Steven Galson, another newcomer who was brought into FDA (in April 2001) to oversee expansion of drug safety activities. Formerly with the Environmental Protection Agency, Galson has been serving as CDERs acting director during director Janet Woodcocks temporary assignment to the FDA commissioners office to develop the agencys counter-bioterrorism plan. 

One unanticipated task for Galson and Seligman will be to appoint a new director for ODS following the departure of Peter Honig, former head of OPDRA and briefly of the new drug safety office. Honig left FDA last month to direct a new risk management office at Merck, a move reflecting the companys interest in emphasizing product safety and risk management strategies as part of its product development programs. As vice president of risk management, Honig reports to Merck executive vice president of clinical sciences and product development, Douglas Greene. 


CDER will gain added advice on drug safety issues from a new advisory panel on Drug Safety and Risk Management. Because of federal government restrictions on establishing new advisory committees, the new panel is a subcommittee of CDERs Advisory Committee for Pharmaceutical Science. Patient safety expert Peter Gross, MD (chairman, Department of Internal Medicine, Hackensack University), chairs the patient subcommittee that will provide FDA with input on methods of risk assessment, management, and communications.

Among the experts in risk communications, clinical trial methodology, biometrics, and pharmacoepidemiology on the 10-person panel are Michael Cohen, RPh, MS, DSc (president, Institute for Safe Medication Practices), and Curt D. Furburg, MD, PhD (Department of Public Health Sciences, Wake Forest University). In a journal article analyzing the review and withdrawal of Bayers Baycol (cerivastatin) last year, Furberg noted that large, long-term clinical trials often are needed to evaluate drugs prescribed for chronic use. He has raised questions about the use of surrogate endpoints, such as lipid markers, in approving lipid-lowering agents and about long-term risks related to calcium channel blockers. 

At its first meeting, set for 23 April, the new subcommittee is slated to review safety concerns related to GlaxoSmithKlines irritable bowel syndrome therapy, Lotronex (alosetron). Glaxo pulled that new product off the market in November 2000 because of serious adverse events and an inability to reach agreement with FDA on a risk management program. At the April meeting, Glaxo is expected to present safety data derived from Phase 4 studies underway at the time of withdrawal. The session also will provide an opportunity to evaluate FDA risk management proposals and safety strategies available to sponsors.


In addition to expanding agency structure for overseeing medical safety and risk issues, FDA is working on a number of policies and programs to enhance the safe use of drugs and to reduce medication errors. For example, CDER epidemiologists are weighing new techniques and modeling methods for analyzing clinical trial safety databases. FDA also is developing proposals and guidances to reduce confusion related to drug trade names, labeling, and packaging. 

A lead initiative involves revision of the content and format of professional labeling for drugs and biologics, which has been in the works for several years. Manufacturers have been concerned that the agencys proposal to revise drug labeling will make prescribing information much longer, requiring costly changes in manufacturing and packaging operations. An added fear is that the proposal to include important prescribing information in a highlights section would open manufacturers to liability charges. FDA officials believe that the new format will make it much easier for practitioners to gain important prescribing information and to ensure the safe use of medicines. To soften the impact on industry, the agency may apply the new requirements initially to new products and permit manufacturers to phase in changes for previously approved drugs over time.


Mercks move to hire FDAs Honig as vice president of risk management reflects increased interest among manufacturers in giving drug safety issues more prominence. Officials at FDA and PhRMA (Pharmaceutical Research and Manufacturers of America) have formed a risk management tool kit committee to reach consensus on new approaches to drug safety problems. Agency officials have complained that FDAs limited regulatory authority allows it only to revise product labeling, require a manufacturer to send letters about safety concerns to health professionalsor require withdrawal of a medicine from the market.

CDER officials recognize that the current tools often are not very effective in bringing about changes in prescribing or patient use of certain therapies, but they often are reluctant to ban distribution of an effective therapy. To provide more options, ODS plans to develop a more systematic approach to selecting methods for managing risk and assessing the effectiveness of those methods. The ultimate aim is to develop certain off-the-shelf systems that can be applied to all drugs that require risk management. 

These issues will be part of continuing discussions about the scope and focus of the next phase of the Prescription Drug User Fee Act, PDUFA III, which is set for reauthorization by the end of September. CDER would like to have a portion of user fee revenues available to support expansion of adverse event reporting systems, for development of additional guidance documents on safety reforms, and for devising new risk management approaches. Industry is wary of expanding user fees to cover more FDA activities, but may consider added payments to support certain postapproval programs.

CDER plans to issue a white paper on risk management later this year. It will define the problem and describe approaches for addressing risk and future objectives. The agency also has been developing an extensive proposed rule on postmarketing drug risk surveillance, which also may appear later this year. All these initiatives affect the testing and marketing of new drugs and put safety issues in the forefront of product development and distribution.            

View from Washington

FDA is revising policies to ensure that clinical studies generate sufficient data to ensure the safe use of new medical products.

Safety and Risk Assessment Gain Importance

The regulations governing the transportation of infectious and diagnostic substances are becoming ever more stringent. Ignorance of the latest requirements and procedures could lead to noncompliance, which could have potentially catastrophic consequences for clinical trial programs. This statement from the registration form for a 2001 biomedical seminar sums up the situation facing clinical trials professionals who must see that potentially hazardous substances are transported to laboratories for analysis.

The seeds for this article were sowed when I heard of a Federal Aviation Administration (FAA) inspection at a U.S. clinical trial site, with possible ramifications for the investigator and sponsor. I discovered that other clinical researchers had no more information than I. Although most investigator meetings offer brief presentations about sample shipment, there is some question whether that constitutes adequate training of site personnel. Site personnel at those meetings are usually investigators and study coordinators, neither of whom may actually handle the samples. 


Global trials have been increasing since the development of a single review process for European approval and ICH bridging-development strategies. When a central laboratory is used for analyzing critical specimens, those specimens must be shipped across national borders. The central functions provide validated data for study centers and promote approval on a worldwide basis. Challenging aspects in each geographical region include

	country-specific import and export requirements.

	temperature differencesfor example, extreme heat.

Central laboratories cannot obtain country-specific permits. The investigator or someone representing the site must apply in person and the individual country import requirements must be known ahead of time.

Depending upon the geographical location, a multitude of transport agencies can be involved. Although each country may have different laws, the International Air Transport Association (IATA, see box) publishes industry standards for shipping hazardous materials via air in its annual Dangerous Goods Regulations manual. 

Regulations frequently change. If there are no applicable local/national regulations, it is up to the shipper, courier company, and all involved parties to follow international regulations for example, IATAs. Before clinical trials begin in a country, a sponsor must work with an international courier company to identify what permits and paper work are required. Currently, clinical site personnel are considered the originators, but study sponsors may share liability in the future. 


Currently, FAA inspectors (as agents of the U.S. Department of Transportation, or DOT) visit airlines and shipping companies. They also visit freight forwarders and other shippers such as investigators and laboratories. The Research Roundtable Web site (www.researchroundtable.com/ FAA%20Regulations.htm) describes a visit to an Idaho clinical research center by an FAA inspector who requested training records for the people identified on the shipping bills. The packaging was found to be acceptable, but there were no training records. DOT procedures require three training components for hazmat employees (those dealing with hazardous materials): general awareness, function-specific, and safety training. Few sponsors and investigator sites are aware of these requirements. Although the Idaho case is pending as this is written, fines seen on the FAA Web page range from $1,500 to over $200,000. 

The DOT currently allows retraining up to three years after the original training dateor whenever the regulations change within that three yearsbut the International Civil Aviation Organization and IATA require recurrency training within two years of the initial training class (unless a regulatory change mandates training before the end of the two years).

Even if your central laboratory provides all the correct packaging and labeling for the air shipment of these infectious substances, site personnel must still undergo training and testing. Any person packing or shipping hazmat must be trained.

In an interview with The Research Roundtable, Thomas Kenny (manager, FAA Dangerous Goods Program for the Northwest Mountain Region) explained that shippers have to be trained. Its nice that they have the boxes and packaging materials, but they have to be trained, and it has to be function-specific training. He pointed out that a company could have sent some labels or a certification form for a shipper to use that may, in fact, be incorrect.

This issue has only recently emerged among clinical researchers because, as Kenny stated, the FAA has shifted its focus from what happens at airports. Now, he said, they are looking upstream to shippers.

Similarly, a story from a quality assurance friend described a July 2000 FAA audit of an infectious disease site for a pneumonia study that ended a year earlier. The FAA auditor appeared at the LA clinic without notification. He asked the site several questions about the FedEx printed airbills and preprinted Hazardous Goods forms. Not satisfied that the site staff was knowledgeable, the auditor cited them for not knowing about hazards and levied a fine of $150,000which was later dropped. The auditor told site personnel that attending the investigators meeting and initiation visit and that receiving and using a laboratory manual were insufficient. Instead, they needed some sort of official documentation from a training program approved by a competent authority. The site secured training from a local environmental management company. 


Currently, the sponsor has no legal responsibility to the FAA for shipments made by the investigator or other site personnel. FAA personnel are considering a change to that rule. Although there is not yet even a proposal for making sponsors responsible, it is prudent for pharmaceutical companies to ensure that the institutions they chose as investigative sites are safe to contract with.

The governments of the United Kingdom, The Netherlands, France, Turkey, and Australia are more active on this subject than most other countries. The FAA can inspect airline operations in countries outside the United States if a U.S. airline flies into or out of that country. The 

 obligates any company that imports to the United States to inform foreign companies of U.S. federal regulations. 

The CFR defines diagnostic specimens and biological products. The terms infectious substance and etiologic agent are synonymous. (49 CFR 173.134)

 Under current FAA practice, blood specimens being shipped to a central lab for an infectious disease screeninghepatitis testing, for examplewould be considered dangerous. But blood sent for a cholesterol determination or routine chemistries would not be considered dangerous. Presumably, such nondangerous shipments would not require training. FAA rules can be confusing because most medical personnel follow universal precautions and handle all blood and bodily fluid specimens as biohazardous materialseven specimens to be screened to see whether a potential subject meets the inclusion/ exclusion criteria for a noninfectious disease study. 

Transfer is change of possession or ownership with permits, licenses, and registrations issued by federal agencies involved in import, export, and domestic transfer. Transport includes packaging, labeling, and shipment.

The Centers for Disease Control and Prevention (CDC) also have a regulatory role and complies with the following U.S. Public Health Service regulations: 

	42 CFR 71.54, Etiologic Agents, Hosts and Vectors

	42 CFR 72.6, Interstate Shipment of Select Agents with additional requirements facilities.

Import permits are issued for diagnostic specimens, infectious substances, microbial toxins, select agents, and hosts/vectors of human disease (for example, bats). Import material must be packaged and labeled according to 42 CFR 72, 49 CFR 171178, and IATA Dangerous Good Regulations (DGR), and must be handled in accordance with the CDC/NIH guidance, Biosafety in Microbiological and Biomedical Laboratories. Exemptions to these permit requirements include attenuated vaccine strains, CLIA certified laboratories, clinical specimens, and toxins.

Select agents include certain viruses, bacteria, rickettsiae, fungi and toxins, and genetically modified/genetic elements. A Final Rule for Select Agents (42 CFR 72.6) was added to existing regulations and published in the Federal Register 24 October 1996 and effective 15 April 1997

 was instituted in response to a few bioterrorist incidents. Previously, there had been no requirements for licensing or registration of facilities transferring certain human pathogens, nor had there been any safety requirements for these facilities. With increased fears over recent terrorism activities, scrutiny and care will increase in this area as well. For packaging, labeling and shipping select agents, existing requirements include IATA Dangerous Goods regulation, DOT/CDC Federal shipping regulations (49 CFR 72 and 49 CFR 171178) with the additional requirements of CDC registration, and EA-101 tracking. In summary, the transfer of certain biological agents (select) is restricted. U.S. shipping/receiving facilities must be registered with CDC, and CDC must be notified of all shipments (EA 101, www.cdc.gov/od/ohs).


The UN Committee of Experts on the transport of Dangerous Goods has established a new provision to clarify that diagnostic specimens must be assigned to the category UN 3373 unless the source has or may have a serious disease in which case it must be assigned to UN 2814 or UN 2900. These are categories based upon known medical histories, endemic local conditions, patient symptoms and professional judgement about individual circumstances. A note has been proposed to clarify that blood collected for blood transfusion or for the preparation of blood products and any tissue or organs intended for use in transplant are not regulated for transport.


Dangerous goods include articles such as oxygen generators, fuel control units, flammable gas torches, fireworks, infectious specimens, culture isolates, and dry ice. Dry ice is considered a hazardous substance because it expands as it sublimatesthat is, reverts from solid back to gas. If the expanding gas cannot escape, the container may rupture and release its contents.

The IATA manual based on the ICAO Technical Instructions outlines the procedures for safe transport. The regulations state that the shipper (an investigator site, for example) is responsible for ensuring proper staff training (see Dangerous Goods Training box). Carriers are required to follow the IATA regulations and additional national regulations. Some confusion is caused by the many terms used to describe noninfectious specimens. Many people use the term diagnostic specimen to describe a noninfectious sample. The Centers for Disease Control and Prevention (CDC) use the term clinical specimen when referring to a noninfectious sample. The DOT does not currently regulate diagnostic specimens, but this will change because of a soon-to-be-released Notice of Proposed Rulemaking (NPRM) addressing infectious and noninfectious specimens (HM 226).

 IATA uses the World Health Organization (WHO) Risk Groups to determine whether a diagnostic sample needs to be shipped as infectious (using Packing Instruction, PI 602) or noninfectious (using PI 650). Noninfectious diagnostic specimens currently are defined in the IATA regulations as specimens with a low probability that WHO Risk Group 2 or Risk Group 3 pathogens are present in the sample. 

PI 602 is used for shipment of infectious substances. UN specification packaging must be used. This requires testing of the whole package as prepared for transport, but such testing is not always available in most of the world. Indications are that customized packaging designs will increasingly be used and work is under way internationally to simplify requirements. Countries have different laws. For example, routine clinical samples are not shipped as infectious in the United States if the probability of pathogens is low (for example, HEP or HIV). In this case, the clinical laboratory sample package can be labeled as diagnostic.

Liability/responsibility lies with the shipper, which is why training of personnel such as those at clinical sites is becoming such a required issue. Personnel are expected to know and declare that a specimen source has, or may have, a serious disease and that it should be labeled infectious. Air France personnel, however, are said to consider all blood samples as possibly infectious, so they will not accept any bodily fluids unless they are packaged and labeled as infectious substances. Currently, IATA regulations require a shipper of noninfectious diagnostic samples to mark the package and the paperwork as Diagnostic Specimen packed in compliance with Packing Instruction 650.

Biological products are derived from living organisms and are manufactured and distributed in accordance with the requirements of the national government. These are used for prevention, treatment, and diagnosis of disease. A vaccine would be an example of a biological product. Most biological products are noninfectious but in some cases when pathogens are present, they may need to be packaged and shipped according to IATA PI 602. PI 602 is used when packaging and shipping an infectious substance. You can see where the confusion begins and continues.

Shippers would like one packaging standard for infectious and diagnostics shipments. A special provision (A81) was amended for infectious substances for air travel; it became effective 1 July 2001 and covers all body fluids provided they do not contain pathogens in Risk Group 4.

Regulating agencies have some conflicting and confusing requirementsbiohazard labels versus infectious substances labels, for example. DOT does not require the use of a biohazard label, but OSHA rules require that it be used in some instances (although not for infectious substances that are already properly labeled). Some airlines refuse to carry packages with biohazard labels because they believe the package may contain infectious materials. Debates continue over this issue. 

Site visitsresolution considered by one pharmaceutical company


One company has considered having an FAA/DOT trainer train all the clinical research associates. Then, at the initiation visit, the CRAs would train site staff who will be involved in shipping samplesand provide documentation of the training. Some mechanism for monitoring changes to the regulations and a way to determine when retraining is required also need to be in place. This degree of training may not be considered certified (fully acceptable) by an FAA inspector, but would be evidence of sponsor and investigator dialogue.


FAA has recently hired approximately 170 additional inspectors following an air crash and this activity has escalated to more than just laboratories and includes shipping sites such as hospitals which are flagged by reviewing airline records. Because of the 11 September 2001 terrorist attacks in New York, FAA practices and philosophies may change. If perceived risk leads to increased scrutiny, costs could escalate.There are different types of trainingfor example, general awareness, function specific, and safety. Fines have been levied and then reduced once sites can prove or initiate training.

The regulations and definitions are changing for national and international groups. Liability is usually limited to the employer which in clinical trials is usually the investigator, but it could be argued that the sponsor is the employer as we contract with investigators to conduct studies according to protocols which include preparation and shipment of samples. A sponsor should also be concerned about possible civil court actions if there is an injury (for example, transmission of an infectious disease) to a cargo handler. 

Companies such as Lilly, Merck, Abbott, and Glaxo have become increasingly involved in organizations that are advisory observers to a UN expert board. 

Pharmaceutical companies should develop policies that define sample categories and outline procedures for personnel to follow, which may include that site personnel have documented training. It is our ongoing responsibility to stay informed of changing regulations, and collaborations with transport agents such as World Courier can be of great assistance. Each sponsor company must develop its own risk management practices and at a minimum, inform investigators of their obligations and provide information on training programs.


1.	World Courier, on 20 April 2001, Miami Beach, FL, on Global Transportation of Infectious and Diagnostic Substances.

2.	World Courier, on 20 April 2001, Miami Beach, FL, on Global Transportation of Infectious and Diagnostic Substances.

3.	World Courier, on 20 April 2001, Miami Beach, FL, on Global Transportation of Infectious and Diagnostic Substances.

4.	Code of Federal Regulations, Title 49, Part 173, Section 134 (U.S. Government Printing Office, Washington, DC.)

5.	Johnson, Guy P., CPA, MS, Investigative Sites: Are You Prepared for an FAA Inspection? Thats Not a TypoThe Federal Aviation Administration is Inspecting Clinical Researchers!, The Research Round Table (February 2001); also at www.researchroundtable.com.

6.	World Courier, on 20 April 2001, Miami Beach, FL, on Global Transportation of Infectious and Diagnostic Substances. 

7.	Code of Federal Regulations, Title 42, Part 72, Section 6 (U.S. Government Printing Office, Washington, DC.)

8.	World Courier, on 20 April 2001, Miami Beach, FL, on Global Transportation of Infectious and Diagnostic Substances.

9.	Neece, Vernon R., manager of Clinical Trial Monitoring and Management, Inveresk Research, personal communication.

10.	Mitchell, Michael, associate director of Logistics, Covance Central Laboratory Services, personal communication.

11.	World Courier, on 20 April 2001, Miami Beach, FL, on Global Transportation of Infectious and Diagnostic Substances.


The author wishes to thank several individuals for reviewing the article and contributing their views, but emphasizes that the viewpoints expressed are their own and not necessarily that of the affiliated organization: Michael Mitchell, associate director of Logistics, Covance Central Laboratory Services; Vernon R. Neece, manager of Clinical Trial Monitoring and Management, Inveresk Research; Michael T. Sweeney, director of Development and Compliance, World Courier Inc.


The International Transport Association (IATA), a trade association of the worlds airlines, was founded by 30 airlines in 1945 in Cuba. Later a special act of Parliament incorporated it in Canada. The association now has over 270 member airlines, which carry approximately 98% of air cargo.

IATA is governed by the IATA Dangerous Goods Board (DGB), which consists of 12 member airlines and is a voting member of International Civil Aviation Organization (ICAO) Dangerous Goods Panel. It participates in the United Nations Committee of Experts (UNCOE). The ICAO is the UN branch responsible for interpreting UN recommendations and publishing these in the ICAO Technical Instructions (TI). IATA first issued Restricted Articles regulations in 1956. Those regulations were adopted by more than 70 countries and are the only international regulations for transporting dangerous goods by air. IATA is working with the World Health Organization (WHO) for maximum global standardization. The 41st edition of Dangerous Goods Regulations came into effect 1 January 2000.

The regulations incorporate all legal requirements of ICAO Technical Instructions as well as airline industry and national requirements. Countries (states) can add additional requirements. Each airline also has the prerogative to be more conservative and restrictive than national regulations.

IATA is not affiliated with the U.S. Department of Transportation (DOT). Each country (state) is the ultimate authority thatas does the U.S. DOTallows the use of the ICAO/IATA regulations within their country.


Peter Napier is head of Business Development for Pivotal Laboratories, a U.S. central laboratory formed in October 1999. At one time, he was responsible for sourcing packaging materials and identifying courier partners for shipping biological specimens. During this process (20 October 2000), Napier said that he was

amazed at how many companies (and individuals) fail to comply with the regulationsparticularly IATA 650 regulations for the transportation of Diagnostic Specimens, although many people still seem to be unaware of the requirement to comply with IATA 602 regulations for the transportation of Known Infectious Samples, even if the presence of pathogens is yet to be confirmed. For example, if we have a study in diabetes, and the drug is known to be hepatotoxic, a hepatitis test may be required at the screening visit. There is a low probability of these samples being infectious, therefore they should be packed in accordance with IATA 650 regulations. If, however, one of the patients is jaundiced, or considered by the investigator to be in a high risk group for hepatitis, then the sample from this patient would have to be classified as Known Infectious, and packed in accordance with IATA 602 regulations. This is despite the fact that the sample is not really known to be infectious at this stage, as the results of the hepatitis test are (obviously) not available.

SIDEBAR: If You Ship Laboratory Specimens

	If your investigative site, hospital, and/or academic medical center ships by overnight air carrier, blood, urine, or bodily fluids that will be tested for an infectious disease (such as AIDS, hepatitis, pneumonia, strep), then these shipments may be classified as Dangerous Goods or Infectious Substances, and your personnel may be subject to FAA regulations.

	If your investigative site, hospital, and/or academic medical center ships Infectious Substances as infrequently as once every two years, then your personnel still may be subject to FAA regulations.

	Even if your central laboratory provides all the correct packaging and labeling for the air shipment of these Infectious Substances, your personnel still may have to undergo training and testing as provided in FAA regulations.

Adapted with permission from The Research Roundtable (www.ResearchRoundtable.com).

is manager of Global GCP Compliance, Biogen Ltd, Maidenhead UK, +44 1628 501 026, email: Mary_OFlaherty@biogen.com.

Clinical trial samples can be dangerous or infectious. With regulators and airlines cracking down, you should know the rules for their transfer and transport.

Transporting Clinical Trial Samples

Fin de sicle is finished in Brussels, and the turn of the century is forgotten. No one is looking backward anymore in millennial mood. Its all eyes ahead for the new challengesand in the field of developing new European medicines, there is everything to play for.

In 2004, the 15-member European Union is likely to become the 25-member European Union, as eight of the former communist states of central Europe join, along with Cyprus and Malta. And by then the aim is to have clearer policies in place for medicines development and regulation. It is not just the clinical trials directive that will beor should befinally in force by then. A wide range of other changes are under way that will also have their effect on the development of new medicines. At stake is partly the efficiency of the mechanisms of the future EU, because it will be much larger, and much more diverse. But equally critical is the extent to which the new regulatory framework will helpor hinderthe European drug industrys ability to stay up with the leaders in international competition.

So right now Brussels is trying to bring several major exercises in the pharmaceutical sphere to a satisfactory conclusion. One is the updating of the EUs authorization systemthe so-called Review 2001 process. Another is a broad-ranging review of how to increase the effectiveness of the European biotechnology industryone of the major themes of the EUs bid to boost growth and employment generally. The third main strand in EU planning is the work of the so-called G10 groupthe 10 top politicians, officials, and drug company executives who have been looking since last year at how to improve European drug industry competitiveness and innovative capacity without crippling European health care agencies with exorbitant drug bills.

As Thomas Lnngren, the executive director of the European Medicines Agency, says in his 2002 workplan,

The European system for the authorization and supervision of medicines, and the EMEA as part of that system, enters 2002 with a number of challenges ahead of it . . . The establishment of effective pharmacovigilance mechanisms for the supervision of medicines. . . the proposals to reform EU pharmaceutical legislation [the Review 2001 exercise] and indeed the role of the EMEA itself. These reforms can be expected to come into force at the same time as the European Union welcomes new member states. This is a unique opportunity to integrate the planning and preparation processes for these two events . . . Our focus will also be on preparation for a number of other initiatives, including our future responsibility for the developments and operation of the EU pharmaceutical regulatory IT strategy from 2003 onwards, the implementation of the directive on clinical trials by 2004 at the latest . . . measures to further improve transparency of the regulatory system . . . and the need to improve scientific advice to the European research-based pharmaceutical industry, [and to] develop our activities in relation to orphan medicinal products.

For biotechnology, the European Commission adopted at the end of January what it termed a major policy initiative for the development of life sciences and biotechnology in Europe. This strategy paper includes an action plan with recommendations for member states, local authorities, industry, and other stakeholders. Its stated aim is to help Europe master the frontier technologies that could make a major contribution to the goal, set at the March 2000 Lisbon European Council, of becoming the worlds most competitive, knowledge-based and sustainable economy within a decade.

It is of key importance for Europe to master the new frontier technologies, which will be at the core of a knowledge-based economy. Life sciences and biotechnology are developing rapidly and globally and have given rise to intense public debate. Europe needs to address the challenges of biotech by developing responsible policies to exploit these new opportunities in a manner that is consistent with European values and standards. Commitment to fundamental ethical values will be crucial to build confidence and foster public acceptance of new biotechnology. With this initiative, the Commission sends a strong signal to the public and private actors who must work together for Europe to be successful.

According to the Commission, Europe is faced with a major policy choice. Either we accept a passive role, and bear the implications of the development of these technologies elsewhere, or we develop pro-active policies to exploit them in a responsible manner. Life sciences and biotechnology are widely recognized to be, after information technology, the next wave of technological revolution in the knowledge-based economy, creating new opportunities for our societies and economies.


With all this focus on forward progress, and on developing an efficient and effective enterprise culture, why is it then that there is a curious redolence of the past in some of the emerging thinking? Most notably, the latest draft of the G10 proposalswhich are due to be finalized and published in Aprilcontains some eerie echoes of 

It urges, for instance, The creation of the European virtual institutes of health, connecting all existing competence centers on fundamental and clinical research into a European network of excellence. It is not just the evocation of Orwells Ministry of Truth that disturbs. There is a curiously corporatist, almost totalitarian, tone to the explanation of the concept.

On the face of it, the logic of the basic proposition that European research is very fragmented is hard to fault. An effective dynamic science base in Europe is fundamental to ensuring the continuing development of innovation and research in the pharmaceutical industry in the EU, the group argues, adding, However, the effective exploitation of the science base in the EU is hampered by relatively weak links between research centers in different member states. The science base is often further fragmented between member states due to poor collaboration between public and privately funded research.

But the G10 recommendations on how to deal with this fragmentation might almost have slipped from the pages of a Stalinist five-year plan. The group believes that to exploit effectively the high quality research that exists in Europe there has to be much greater integration of research across national borders within the EU. This should help foster a critical mass of research in particular areas and allow much greater commercial exploitation of research. One almost searches instinctively for a footnote giving figures on tractor production and wheat yields. Some entrepreneurial spirits in the European pharmaceutical industryeven within clinical development divisionsmay recoil from this all-join-hands-and-work-for-the-common-good approach. There are other ways of driving commercial success.

Similarly, there is slightly sinister tone to the passage on incentives for researchwhich adopts a particularly dirigisme approach to clinical trials. The greater integration of the European science base must be actively supported at EU and member state level. The coordination of clinical trials on a European scale would help to make existing clinical trials more effective and reduce the risk of duplication. Underpinning this with a database on clinical research results would provide an invaluable tool to researchers, both public and private, throughout Europe.

Of course many researchers and clinical trial staff in the private sector have frequently expressed interest in the possibility of greater access to some databut not usually with quite such enthusiasm for coordination from some higher authority, nor with quite so much scorn for theoften inevitablerisk of duplication. For this reason, there is a hint of a double-edged sword in the terse G10 recommendation at the end of this section of its draft conclusions: Commission and member states co-ordinate and support the conduct of clinical trials on a European scale, establish a database on clinical research results.

And again, in a prose-style drawn from Kafka, the shadow of Big Brother (the Orwellian despot) falls across a passage about the need for greater coordination of assessments of relative efficacy. 

The existing EU regulatory structure governing the control of medicines is focused on ensuring that all medicines meet high standards of quality, safety and efficacy. Member states are increasingly supplementing this with national requirements concerning the relative clinical and cost-effectiveness of new medicines to ensure the efficient use of increasingly scarce resources. Although the assessment of relative effectiveness is a matter for national competence there could be value in facilitating the exchange of information on national practices between member states.

The G10 draft maintains, with all the clarity of a bureaucratic nightmare, This increased transparency should improve the quality, consistency, and speed of reimbursement and pricing decisions across the EU and provide industry with a clearer understanding of the criteria used and the reasons for their use.


This looks dangerously like Newspeakthe Orwellian language rendering acceptable the unacceptable. The drug industry is largely hostile to the idea of relative efficacy assessments anyway, and doesnt want it to spread from the countries that exercise it to the ones that dont. So there is probably no value in facilitating the exchange of information. Quite the reverse. In addition, why should anyone believe that this increased transparency will in any way speed reimbursement and pricing decisions? There is no reason whatever (or certainly no justification advanced) for the suggestion. And as for providing industry with a clearer understanding, this sounds like being given a detailed life-size photograph of the guillotine before having your head chopped off. It is an insult to suggest it could be any sort of benefit.

Nonetheless, the draft of the G10 group recommends that 

The Commission should organize a European reflection to explore how member states can improve ways of sharing information and data requirements to achieve greater certainty and reliability for all stakeholders, even if the decisions they take may differ. The objective is to improve the value of health technology assessment, and to share national experiences and data while recognizing that relative evaluation should remain a responsibility of member states. Member states should be encouraged in developing systems to focus equally on assessments of clinical and cost-effectiveness. 

Game, set, and match to the Thought Police.

Part of the menace of this document lies in the studious neutrality of the language employed. It has an utterly soulless quality, purring on evenly like a motor yacht across some of the most contentious issues in EU drug provision, without so much as an acknowledgement of the troubled waters it is navigating. It is of a piece with the rest of the document; and its recommendations are, in some areas, of a banality that almost defies beliefyet delivered with the same imperturbable sonority.

On pharmacovigilance, for instance, it says: Once medicines are authorized to be placed on the market, industry and national regulatory authorities undertake regular monitoring to ensure that they continue to meet the required standards of safety, quality, and efficacy. This is a vital role played by national regulatory authorities and critical to the continuing confidence EU citizens have in the medicines they are using. Incontrovertible, of course. But utterly self-evident. And the recommendation it makes is, accordingly, no more than the most obvious commonplace: That systems for postmarketing surveillance should be optimized to ensure that coordinated processes are in place to gather data on adverse events and patient safety.

The EU proposals on biotechnology are also dappled with tones of public as well as genetic manipulation. Boiled down to its simplest form, much of the Commission plan is to get public opinion on its side. If its strategy were really clear, it would probably say, We, the Commission, know that biotech is a good thing. Public opinion in Europe is causing some national governments to put brakes on its progress. Were going to change that. Were going to persuade everyone it is a good thing. But were not going to use crude propaganda. Were going to infiltrate public opinion through supposedly objective debatesjust as long as they lead to the conclusion we want. But what the Commission actually says is: The strategys cooperative and consistent approach to fostering sustainable development is designed to address the complex ethical and societal concerns and support the broad public debate. In line with the principles of governance, the initiative is based on a wide public consultation that included a conference with a broad range of stakeholders. Sound familiar?            

View from Brussels

Facing an immediate future of rapid growth, the EU is looking to clarify its clinical trials policies, but it?s having some problems.

Applied Clinical Trials-03-01-2002