v7.4 - advance - fall 2010

With more clinical trials moving from the U.S. and Western Europe to emerging regions in Asia, Latin America, Eastern Europe, and Africa, it becomes increasingly important for research sites in those areas to demonstrate that they can meet in-ternational standards for protecting participants in human research.

The number of clinical research sites outside of the U.S. continues to grow, most likely because costs can be 50 to 60 percent lower. Between September 2007 and December 2008, for example, the number of U.S. clinical research sites dropped 4.3 percent, or 6,492 sites. Eastern Europe added 2,532 sites; Asia, 2,138 sites; South America, 1,358; and the Middle East, Africa, and Australia, a total of 465 sites, according to Clinical Trial Magnifier.i

A recent report of the Office of the Inspector General noted that nearly 6 percent of research sites listed in mar-keting applications approved by the Food and Drug Administration (FDA) in fiscal 2008 were in Asia, 5 percent in Latin America, over 6 percent in Central and Eastern Europe, and just over 1 percent in Africa.ii

FDA faces challenges

The report said that FDA inspected investigators at 1.2 percent of all clini-cal trial sites for applications approved that year, including 1.9 percent of sites

in the U.S. and 0.7 percent of foreign clinical trial sites.iii

Meanwhile, 80 percent of market-ing applications for drugs and other biologics approved by FDA in fiscal 2008 contained data from trials con-ducted outside the U.S., according to the report. More than half of all research participants and research sites were in foreign countries.

Many drug and device manu-facturers conducting multiregional clinical trials have been following

FALL 2010

Shift from Helsinki to ICH-GCP Leads to Single World StandardThe Food and Drug Administration (FDA) now allows foreign research sites and the sponsors of the studies conducted in those sites to follow good clinical practice (GCP):

“Accept as support for an IND (Investigational New Drug) or application for marketing approval a well-designed, well-conducted, non-IND foreign clinical study, if it was conducted in accordance with GCP and we are able to validate the data from the study through an onsite inspection, if necessary.” 1

In April 2009, FDA replaced the requirement that such studies be conducted in accordance with the Declaration of Helsinki— principally a document of ethical principles rather than performance standards—with a requirement that the studies be conducted in accordance with GCP, including review and approval by an ethics committee (EC).

Although FDA did not specifi-cally incorporate ICH-GCP (E6) into the proposed revision of

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Emerging Markets Can Demonstrate Equal Protections

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Are You Following Good Clinical Practice?

Korean Medical Centers Join Accreditation

Respondents Compare Client Performance

AAHRPP 2011 Conference

From thePresident & CeO

C O N T I N U E D O N PA G E 6


21 CFR Part 312.120, it stated that the standard of GCP in the revised regulation was consistent with that in ICH-GCP (E6) and was sufficiently flexible to accommodate differ-ences in how countries regulate the conduct of clinical research while helping to ensure adequate and comparable protection of research participants.

ICH-GCP (E6) incorporates the principles of the Declaration of Helsinki into its guideline. In addi-tion, it defines GCP as “an interna-tional ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.”

The guideline states, “Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are pro-tected, consistent with the principles that have their origin in the Declara-tion of Helsinki, and that the clinical trial data are credible.”2

Regulators and industry

ICH brings together regulatory authorities and experts from the pharmaceutical industry to discuss scientific and technical aspects of product registration.

However, unlike the general principles outlined in the Declara-tion of Helsinki, ICH-GCP provides more detailed operational guidance

and has been adopted as a unified standard worldwide. Any country that adopts the guideline follows the same standard.

The purpose of ICH-GCP is to achieve greater harmonization in the interpretation and application of technical guidelines and require-ments for product registration, in order to reduce the number of tests or avoid the need to duplicate tests carried out during the research and development of new medicines.

Harmonization more economical

Harmonization is a more economi-cal use of human resources, and it eliminates unnecessary delay in the global development and availability of new medicines by maintaining safeguards on quality, safety, and efficacy and by satisfying regula-tory obligations. In fact, ICH-GCP (E6) is now the primary guideline for conducting multinational clinical trials and has provided impetus for the global expansion of industry-sponsored studies.

In order to foster one standard worldwide, AAHRPP accredits hu-man research protection programs to the ICH-GCP (E6) guideline, in

addition to local laws, worldwide. Dr. Peter Vasilenko, Vice President of Accreditation at AAHRPP, discusses how to apply the guideline in his column on Page 3.

While some have criticized the use of foreign trials to support market-ing applications in the U.S., the fact is that of all the clinical trials sponsored by U.S. and European companies, most are still conducted in the U.S. and Europe. Still, trials are migrating to emerging markets, and that trend is unlikely to change (see accompanying article on Page 1). Thus, it is imperative that those clinical trials are conducted under high ethical standards that build public trust in the research enterprise around the world.

— Marjorie A. Speers, Ph.D.

1 21 CFR 312.120.

2 U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) Guidance for Industry, “E6 Good Clinical Practice: Consolidated Guidance,” April 1996, p. 6.

2 A A H R P P A D V A N C E

AAHrPPAdVAnCePublished quarterly by the Association for the Accreditation of Human Research Protection Programs, Inc., 2301 M Street, N.W., Suite 500 Washington, DC 20037, (202) 783-1112 [email protected], www.aahrpp.org.

PResiDent & CeO: Marjorie A. Speers, Ph.D.

eDitOR: David Ward

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Todd Allan Printing, Co., Inc., Beltsville, MD

COPyRIGHT © 2010 By THE ASSOCIATION fOR THE ACCREDITATION Of HUMAN RESEARCH PROTECTION PROGRAMS (AAHRPP®). ALL RIGHTS RESERVED.

From thePresident & CeOC O N T I N U E D f R O M PA G E 1

ICH-GCP (E6) is now the primary guideline for the conduct of multinational clinical trials and has provided impetus for the global expansion of industry-sponsored studies.

A A H R P P A D V A N C E 3

By Peter Vasilenko, Ph.D. Vice President of Accreditation, AAHRPP

Here’s a common scenario: The Office of Sponsored Programs of an organization negotiates a clinical trials agreement (CTA) for a multi-site clinical trial. The CTA states that the organization will follow the In-ternational Conference on Harmoni-zation—Good Clinical Practice (E6), commonly referred to as ICH-GCP.

The investigator probably does not know or pay attention to the fact that this stipulation is in the CTA. He or she believes, though, that “of course, we follow good clinical practice.”

ICH-GCP (E6) is a 59-page docu-ment with several requirements that fall outside U.S. regulations and that many investigators and IRBs in the United States do not follow. Some requirements are even contrary to standard U.S. IRB practice.

For example, ICH-GCP 4.8.1. states: “Prior to the beginning of the trial, the investigator should have the IRB/IEC’s written approval/favorable opinion of the written informed consent form and any other written information to be provided to subjects.” In other words, the investigator is required to tell the research participant that the IRB has approved the research, a concept that is generally not applied in the U.S. In fact, most IRBs argue against telling the participant that they have approved the protocol, because the “endorsement” of the IRB might be perceived as coercive.

Make sure you know and follow iCH-gCP (e6)

AAHRPP takes no position on whether an organization makes

a commitment to following ICH-GCP (E6), but its standards require that if an organization does pledge to follow the guideline, it should know and implement the require-ments. As part of the evaluation for accreditation, AAHRPP requires the organization to follow all laws and regulations to which it is bound and any guidance to which it voluntarily commits itself.

To help organizations that follow ICH-GCP (E6), AAHRPP has devel-oped a Tip Sheet entitled Following the Guideline of the International Conference on Harmonization—Good Clinical Practice (E6), which is avail-able on the AAHRPP Web site.i The Tip Sheet provides the ICH-GCP (E6) requirements that are not found in the FDA or DHHS regulations.

ICH-GCP (E6) is an ethical and scientific quality guidance document that is used internationally in the conduct of clinical trials. It includes areas for designing, conducting, recording, and reporting research that involves human participants. The guideline has its origins in the Declaration of Helsinki and contains the following sections:

1. Glossary.

2. The Principles of ICH-GCP.

3. Institutional Review Board/ Independent Ethics Committee.

4. Investigator.

5. Sponsor.

6. Clinical Trial Protocol and Protocol.

7. Investigator’s Brochure.

8. Essential Documents for the Conduct of a Clinical Trial.

You have several options

So what should your organization do? First, before even thinking about negotiating CTAs, your organization has to decide how broad a commit-ment it is willing to make. There are several options. The simplest is to decide to follow ICH-GCP (E6) with the addition of the phrase “as ad-opted by FDA.” This means that you will follow good clinical practice as outlined by FDA,ii which is basically complying with the FDA regulations and excludes those additional requirements in ICH-GCP (E6) that are not found in the FDA regulations.

Another option is to limit the types of research to which your orga-nization applies ICH-GCP (E6). For example, apply ICH-GCP (E6) only to international clinical trials. Or, a third option is to limit the sections of ICH-GCP (E6) your organization applies, such as only following the IRB section (3). Note, however, that the consent requirements are in the investigator section (4.8), not the IRB section. If you choose to limit the application of the ICH-GCP

Are You Following Good Clinical Practice?A Primer on iCH-gCP (e6)

ICH-GCP (E6) is a 59-page document with many requirements that fall outside U.S. regulations and that investigators and IRBs in the United States do not follow. Some requirements are contrary to standard U.S. IRB practice.



The Catholic University of Korea Catholic Medical Center and Sever-ance Hospital, Yonsei University College of Medicine—with two of the top-ranked medical schools in Korea—recently joined the growing number of research institutions ac-credited outside the United States.

In the past few years, the Republic of Korea has increased its capacity for conducting clinical research, supported by the nation’s Promotion of Industrial Education and Industry-Academic Cooperation Act. As a result, both institutions are conduct-ing growing numbers of such studies.

severance Hospital

Severance Hospital was founded in 1885 by an American medical missionary, Horace N. Allen, M.D., who was given the opportunity to save the life of the queen’s nephew.

In gratitude, the king founded what was to become Severance Hospital, under the direction of Dr. Allen.

The hospital has since expanded to include 1,500 physi-cians, who see about 2 million outpatients and 1 million in-patients a year. It includes the Cancer Center, Rehabilita-tion Hospital, Car-diovascular Hospital, Eye and ENT Hospi-tal, and Children’s Hospital.

The HRPP at Sever-ance has close to 200 researchers, in eight laboratories: immu-nology, molecular biology, cell biol-ogy, medical genet-ics, endocrinology, morphology, medical radiology, and electrophysiology.

The program includes the Human Research Protection Center—directed by Sun Young Rha, M.D.—the IRB, the Clinical Trials Center, the Conflict of Interest (COI) Committee, the Bioethics Committee, and the Legal Team.

The hospital is particularly proud of the level of cooperation between researchers and the IRB. “One of the keys to our success is how well our researchers understand that they can benefit from their interaction with the IRB,” Dr. Rha says. “Both parties learn from each other.”

Competing for international trials

The Yonsei Medical Research Center facilitates collaboration between fac-ulty of its clinical departments and basic medical research scientists, providing opportunities to stimulate new medical knowledge that can ultimately be incorporated into clinical applications.

Another aim of the center is to bring the College of Medicine to a level where it can compete success-fully for multisite transnational clinical trials.

“As a developed country with major urban centers, Korea is a very attractive market for sponsors who want to expand their trials, at lower cost than in the U.S. or Japan,” according to Dr. Rha.

Top Korean Medical Centers Join Accredited Institutionsseeking transnational trials

“As a developed country with major urban centers, Korea is a very attractive market for sponsors who want to expand

their trials, at lower cost than in the U.S. or Japan.”

— Sun young Rha, M.D. Director, Human Research Protection Center, Severance Hospital

Severance Hospital, yonsei University College of Medicine

Seoul St. Mary’s Hospital at the Catholic University of Korea Catholic Medical Center.


History of innovation at the Catholic Medical Center

Like Severance Hospital, the Catholic University of Korea Catholic Medical Center (CMC) has a long history as a missionary-founded medical insti-tution. From the start, it has taken what it calls a “holistic” approach to medicine, incorporating both science and the Roman Catholic faith. With its eight hospitals and nine research centers, CMC has established a sig-nificant track record of innovations in Korea.

Sixty percent of the 650 studies at CMC are clinical trials. Research is funded by 160 pharmaceutical com-panies and 310 government agen-cies and academic councils.

The center originally sought ac-creditation from AAHRPP after its research centers had been selected as a government Regional Clinical

Trial Center. “We were seeking ways to improve clinical research and study ethics for all of the nine CMC organizations,” according to Ryang-soon Lim, Pharmacist / Manager of the Administrative Support Unit for the Office of Human Research Pro-tections at CMC. “We believed that AAHRPP accreditation would allow us to reach such goals.”

CMC’s flagship Seoul St. Mary’s Hospital had already gained recog-nition from the Forum for Ethical Review Committees in the Asian and Western Pacific Region (FERCAP) in 2007. However, because FERCAP recognition applies only to IRBs, AAHRPP’s accreditation of the whole institution made it much more at-tractive in influencing sponsors to conduct their trials through CMC, Ms. Lim explains.

The center predicts that accredi-tation will increase the number of industry-sponsored studies at the

institution by confirming the qual-ity of its research and oversight with international sponsors, according to Ms. Lim. She also expects other Korean organizations to seek accreditation.

CMC is particularly proud of its record in overseeing its clinical trials. For example, the OHRP’s mean number of days from submission of a protocol to approval in 2009 was 28 days for its 12 IRBs, which is signifi-cantly lower than the mean for other AAHRPP clients at 48.8 days.

Just as important, however, is the way accreditation has encouraged CMC to realize its corporate mission of “Respect for Life.” Ms. Lim reports that because the accreditation standards go beyond Korean federal regulations and make the HRPP at CMC more visible, they have in-creased both bioethical awareness and research quality improvement at the center.

Recently, we asked organizations whether they are using the metrics published in the summer issue of the Advance, and they told us they are using them to compare with mea-sures from their own human research protection programs (HRPPs).

In just three weeks after metrics from the data were published on www.aahrpp.org and in the Advance, nearly 88 percent of respondents said they had reviewed the information and 71 percent had already begun bench-marking their organization’s metrics against the published measures.Nearly 70 percent reported using the measures to describe the performance of their HRPPs, while over 72 percent used them to measure quality.

Fifty-nine percent reported using all of the published metrics to make their comparisons. Many selected

particular metrics, such as IRB review times, as particularly relevant.

Half are motivated to collect more data

More than 25 percent of respondents reported that they do not collect data on the performance of their HRPPs. However, nearly 47 percent said they were motivated by the AAHRPP met-rics to collect more such data. Among the data respondents felt motivated to collect were scientific review turn-around times.

Over 42 percent indicated they would like to see additional data collected and analyzed by AAHRPP, including:

n Stratifying the data by program size, size of organization, funding, and staffing levels.

n Analysis by organization type (e.g., academic medical center, independent IRB, hospital, univer-sity, or VA facility), by annual volume of new protocols, and by type of research (e.g., behavioral and social science research or biomedical research).

n Time periods for approvals where electronic systems of submission and review are used.

n Comparing the percentage of studies that is tabled versus conditionally approved.

n Use of a scientific review commit-tee or other “pre-review” process prior to IRB review and the effect of such pre-review on turnaround times and IRB actions.

Want more information

Respondents Comparing Client Performance with Their Own Data


(E6) guideline, make sure that your policies, procedures, and CTAs reflect those limitations.

ICH-GCP (E6) was designed for conducting clinical trials. It is not easily applied to other types of clinical research and certainly not to behavioral and social sci-ence research. So, a word of caution: Before your organization elects to follow ICH-GCP (E6), including all parts and for all research, think care-fully whether you can actually apply it to your entire research portfolio.

The AAHRPP Tip Sheet covers all the requirements that are not included in the FDA and DHHS regulations that you will have to add to your policies and procedures and implement in practice. However, if your organization is not required to comply with the FDA or DHHS regulations and chooses to follow ICH-GCP (E6), then all items in

ICH-GCP (E6) should be followed. Some countries have developed and follow their own version of ICH-GCP.

i AAHRPP Tip Sheet on ICH-GCP: http://www.aahrpp.org/www.aspx?PageID=105$9

ii FDA-GCP: http://www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofScienceand-HealthCoordination/GoodClinicalPractic-esProgram/default.htm

Primer on iCH-gCP (e6)C O N T I N U E D f R O M PA G E 3

the ICH-GCP (E6) guideline for the past 15 years, and FDA has followed suit. Since 2009, FDA has accepted as support for an Investigational New Drug (IND) or application for marketing approval a well-designed and well-conducted foreign clinical study not conducted under an IND when the study is conducted in ac-cordance with GCP and FDA is able to validate the data from the study through an on-site inspection if the agency deems it necessary.iv

One standard worldwide

FDA’s shift to accepting GCP has put FDA in synch with industry standards and practices. In fact, countries outside the U.S. have been using ICH-GCP (E6) as a basis for their own laws, because ICH-GCP is recognized as the worldwide industry standard.

Therefore, both the pharmaceuti-cal industry and national govern-ments have the opportunity to set a uniform standard worldwide for the protection of human research partici-

pants. On the other hand, because most research sites, ethics committees (ECs), and even companies do not fully know or follow all the require-ments in ICH-GCP (E6), progress toward that unifying standard has been slow.

Manufacturers may receive FDA waivers

When sponsors conduct multire-gional studies outside the U.S., FDA regulations allow them to conduct the study under an IND or not. When they choose not to conduct the study under an IND, they must ensure the study complies with FDA regulations, usually by following ICH-GCP. And when they conduct the study under an IND, the inves-tigators must sign Form 1572. This can be problematic because investi-gators cannot always meet all the requirements contained in Form 1572, especially when it comes to ECs. In these cases, sponsors may request a waiver of some of the requirements in 21 CFR Part 56.

FDA guidance states that it “uses the waiver provision only when alternative mechanisms for ensuring

protection of the rights and welfare of human subjects are acceptable.”v

In submitting an IRB waiver request for a foreign study, sponsors must describe the alternative mechanisms for assuring participant protections. However, without a mechanism like accreditation, sponsors and research sites are at a loss to demonstrate that equivalent protections are in place.

i Clinical Trial Magnifier, Vol. 2:2, Feb 2009, Figure 15.

ii Levinson, Daniel R., Office of Inspector General, Department of Health and Human Services, Challenges to FDA’s Ability to Monitor and Inspect Foreign Clinical Trials, Appendix C, Table C-1: “Country Breakdown for Drug-Marketing Applications Approved in FY 2008,” OEI-01-08-00510, June 2010, pp. 30-31.

iiiIbid.iv U.S. Department of Health and Human Services,

Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) Guidance for Industry, “E6 Good Clinical Practice: Consolidated Guidance,” April 1996, p. 6.

v U.S. Department of Health and Human Ser-vices, Food and Drug Administration, Office of Good Clinical Practice, Center for Drug Evalua-tion and Research (CDER), Center for Biologics Evaluation and Research (CBER), “Information Sheet Guidance for Sponsors, Clinical Investi-gators, and IRBs: Frequently Asked Questions – Statement of Investigator [Form FDA 1572],” May 2010, p. 7.

emerging MarketsC O N T I N U E D f R O M PA G E 1

AAHRPP takes no position on whether an organiza-tion makes a commitment to following ICH-GCP (E6), but its standards require that if an organization does pledge to follow the guideline, it should know and implement the requirements.


breakingbarriers

AAHRPP’s 2011 Conference in Washington, D.C. / April 6-8

And get ready to start

Engage with experts who have overcome these challenges, including AAHRPP accreditation directors, executive leadership, government officials, and your peers, on such topics as:

n Choosing risk tolerance over risk aversion in research.

n Unifying divergent institutional committees in the HRPP.

n Achieving global standards of protection for participants.

n Expanding the meaning of collaboration in multiinstitutional human research.

n Infusing quality systems into every aspect of the human research process.

n Building successful university-hospital research partnerships.

n Partnering with the public for better research.

n Collaborating with other IRBs.

n That keep IRBs, administrative officials, and researchers and staff from supporting one another.

n That keep hospitals, academic institutions, independent IRBs, sponsors, CROs, and private research sites from collaborating with one another.

n That keep research participants around the world from being protected by a single, global set of standards.

Mark your calendars for

Contact AAHRPP at (202) 783-1112 or [email protected], or visit www.aahrpp.org for additional information.

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P A i DWashington, DCPermit No. 96

second DOe Lab Accredited AlongWith Five Other OrganizationsWASHINGTON, D.C., September 23, 2010—The Association for the Accreditation of Human Research Protection Programs (AAHRPP) is pleased to announce that it has accredited the human research protec-tion programs (HRPPs) at another six organizations, including a second National Laboratory from the U.S. Department of Energy (DOE).

Brookhaven National Laboratory joins the Pacific Northwest National Laboratory in earning the AAHRPP seal. HRPPs accredited at the September meeting of the Council on Accreditation represent a diverse group of government, for-profit, and academic organizations and bring the total number of accredited HRPPs to 220, representing nearly 1,100 entities.

Following is a list of the newly accredited organizations:

n Brookhaven National Laboratory, Upton, NYn Compass IRB, LLC, Mesa, AZn Mid*Lands IRB, LLC, Overland Park, KSn State University of New York at Stony Brook, NYn The University of Central Florida, Orlando, FLn Tulane University, New Orleans, LA

“These additions to the increasing group of accredited organizations demonstrate that earning AAHRPP’s gold seal is the right and smart thing to assure the protection of research participants,” said Marjorie A. Speers, Ph.D., President and CEO of AAHRPP. “It also increases the number of accredited options for industry sponsors and researchers.”

AAHRPP promotes high-quality research through an accreditation process that helps organizations worldwide strengthen their human research protection programs (HRPPs).

AAHrPPAdVAnCe2301 M Street, N.W., Suite 500Washington, DC 20037

Office: (202) 783-1112fax: (202) 783-1113

[email protected]

april 6-8, 2011foR tHRee DAys of

breaking

barriers at the AAHRPP

Annual ConferenceWashington, D.C.

see Page 7 inside, for details