Transporting Clinical Trial Samples

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.¹

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
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

• cultural factors.
• country-specific import and export requirements.
• time differences.
• airline schedules.
• temperature differencesfor example, extreme heat.
• regulations that may change quickly.

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.²

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.

FAA inspections
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.

Responsibility
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.³

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 Code of Federal Regulations 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)⁴ 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. ⁵

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.⁶

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 1997⁷ 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).

Diagnostic? Infectious? Dangerous?
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.⁸

Dangerous goods training requirements
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.⁹

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).¹⁰ 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.¹¹

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.

Time to prepare
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.

References
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.

Acknowledgements
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.

SIDEBAR: IATAs History and Current Role
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.

SIDEBAR: A Comment from the Field
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

1. 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.
2. 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.
3. 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).

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