Harmonizing
Regulatory Practices Across APEC: Good Clinical Research Inspection
No longer are drug companies restricted to operating within the borders of a
limited regulatory environment. And as a result protecting human research
subjects from any harm can be a challenge. That's why APEC economies got
together in Bangkok to discuss good clinical research practices (GCP) and how to
harmonize standards and their implementation across the APEC region.
The pharmaceutical industry has globalized tremendously, particularly from
the mid to late 1990s. That has led to a number of issues that are very
pertinent to the way clinical research is seen by both governments and industry.
"Certainly there are a number of factors as to why the pharmaceutical
industry as well as clinical research have globalized. Many of these are
economic, including intellectual property protection and the growth of a global
middle class. But there has also been broader government recognition of the
benefits of clinical research in promoting public health and advancing medical
science," said Dr. David Lepay, the U.S. Food and Drug Administration's Senior
Advisor for Clinical Science.
Globalization of the industry happened fairly quickly through corporate
expansion and mergers, creating worldwide networks for product sales. Developed
countries facilitated this change.
Industry began to realize that for credibility purposes there was a role for
regulatory authorities to have a certain level of sophistication within the
countries in which they were placing clinical trials. And governments in both
developed and developing countries understood the need to protect the rights and
safety of their populations. To encourage industry and ensure the quality and
ethical conduct of clinical research, governments and industry recognized the
need to establish and implement international standards.
As the International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH) took hold in the 1990s,
standards were first set for developed countries, including the European Union,
Japan, and the United States.
"But clinical trials could also be accepted by the Food and Drug
Administration (FDA) from outside the US, the European Union and Japan. So there
was a growing interest from industry in establishing bases in other countries,
especially in the developing world, not only to create a marketing presence but
also to place clinical studies. Companies found many economic reasons for this
expansion including active encouragement by many governments. There was also the
perception that research subjects were easier to find and enroll and perhaps
there was less regulatory control in place than in developed countries," said
Dr. Lepay. "More and more studies were thus being placed in an increasingly
larger number of countries."
APEC member economies have been important contributors to this growth.
Pharmaceutical firms across APEC member economies have developed promising new
drugs whose markets are not limited to the economy in which they are developed.
"Companies like U.S.-based Astra Zeneca and Pfizer and Swiss-owned Roche
already have research and development facilities in Ho Chi Minh City and are now
subject to Viet Nam's regulatory authority," explained Dr. Nguyen Ngo Quang who
is Viet Nam's Ministry of Health's Secretary of the Science and Ethics
Committee.
The situation is similar in Singapore. "We would like to develop a good
in-house system to ensure safety of drug development for companies like Pfizer
and Eli Lilly who have sites in Singapore," agreed Mr. Foo Yang Tong who heads
Singapore's Health Science Authority's Clinical Trials Division.
So the GCP principles set forth through ICH for developed countries have
become increasingly adopted as global standards, assimilated into other
international guidelines, and incorporated into national laws and regulation.
These GCP standards reflect internationally accepted ethical and quality
principles and build on many other documents accepted by the international
community.
Laws and regulations, reflecting international GCP standards for the conduct
of clinical research, are now in place in most APEC economies.
"Our laws speak of where we want to go. The GCP is the gold standard and
tells us what we have to do to get there," said Mr. Miguel Gonzalez Guerra,
Chilean Institute of Public Health.
"These practices are the way to proceed in order to carry out clinical trials
because what Chile does is sell the security or give security to the
pharmaceutical companies so that the research is of good quality and the data is
absolutely valid."
For pharmaceutical watchdog agencies, the GCP establishes legal frameworks;
licenses medical professionals and provides mandates to regulatory authority.
Laws and regulations for GCP are important first steps, but the implementation
of these laws and regulations is a critical and continuing challenge. Regulatory
oversight and inspection is a key part of this implementation.
"As recently as 1999, when the U.S. Food and Drug Administration went to
conduct GCP inspections in Australia, we had requests from the Therapeutic Goods
Administration, Australia's regulatory agency for medical drugs and devices, to
accompany us as observers because they didn't yet have any authority to conduct
their own GCP inspections in Australia," said Dr. Lepay.
GCP implementation and inspection were the major themes for the training in
Bangkok; however the workshop also showed how each economy differentiates itself
in its current implementation. For example, Indonesia has legislation in place,
training has been provided, and inspections are underway.
However, while the Philippines has started conducting GCP inspections they
are still working on legislation.
"In the absence of our own official guideline or standard operating procedure
on Good Clinical Practice, we currently adopt international standards like the
ICH Harmonized Tripartite Guideline and supplemental WHO guidance," said Wenzel
Cabotage Asprec, a drug regulatory officer with the Philippines' Bureau of Food
and Drugs.
"Unfortunately, our current human resources are limited so site
inspections are only confined to Bioequivalence testing centers. As
multi-center clinical trial sites for Investigational New Drugs are not
regulated yet, the responsibility of ensuring that the clinical trial is
conducted, recorded, and reported in accordance with the approved study
protocol, SOP and GCP, is largely delegated to the sponsor."
Seeing a need for building the technical skills for the Asia-Pacific region's
regulators, Thailand's Food and Drug Administration undertook an APEC project to
train regulators in Good Clinical Practices and the implementation of GCP.
"In Thailand, it's hard to change the law but we are in the process of
changing the ministerial notification. The new law will indicate broad policy
but this workshop can help us develop the standard operating procedure templates
for regulators and inspectors," said Ms. Akanid Wapeewuttikorn of Thailand's
Food and Drug Administration who organized the project.
"This workshop demonstrates how to conduct an inspection. No university can
teach that. It's really hard to find a course to do this. Some pharmaceutical
companies would teach a GCP audit but it's not the same. Training from
experienced regulators is best.
"Regulators need to inspect for compliance with GCP and our regulations. Now,
I'm prepared to conduct some theoretical training with my colleagues," she said.
Challenge
So how are the responsibilities of sponsors, contract research organizations
and investigators standardized across member economies, and is there reasonable
standard of practice that is recognized internationally?
While some members have put in place standards with which to review clinical
trials and others have passed laws to create a legal framework for these
investigations, regulatory budgets are limited and inspection infrastructures
have not yet been built in many economies.
One of the successes of harmonization has been a fairly rapid acceptance of
GCP standards by governments across the APEC region. While the levels of
implementation vary from one member to another, every one of the economies at
this workshop has adopted international GCP standards in either laws or
regulations. Now, their challenge is to educate colleagues about those standards
and ensure they are being followed by fully implementing the practices.
"To address these shortfalls, the Philippines' Department of Health is
drafting and updating official national guidelines, allocating funds for further
staff training, automating the bureau's systems and processes, and developing an
online trial registry making results publicly available," Mr. Asprec
further explained.
Governments recognize that companies need to remain competitive in the
international marketplace.
In
Thailand, Dr. Yuppadee Javroonget said that Thailand wants to make sure that its
inspectors comply with international practices.
"Undertaking this training has prepared Thailand, as other APEC economies, to
go through with GCP inspections which will ensure that data collected during the
trials are credible," said Dr. Javroonget who heads the Thai FDA's international
affairs division.
"This is important so that reviewers know that scientific evidence supports
the safety and efficacy up to an acceptable level to prove that a product can be
marketed. When a pharmaceutical company develops a product during the clinical
trials, companies can lose lots of money."
Ms. Wapeewuttikorn from the Thai FDA adds: "The life science product is
different than other products. You need to develop the science to create the
product but at the same time you need to develop the control to regulate
something that may be harmful or unforeseen."
"It can also help in quality assurance to prolong the product lifespan in the
marketplace. If a serious adverse event occurs within the first few years of
development, investment risk will be limited," Ms. Wapeewuttikorn further
explained.
Capacity building for the region's drug
regulatory authorities
Organized by the Thai Food and Drug Administration and with staff from the
U.S. Food and Drug Administration who are leading global experts in GCP, medical
regulators from APEC member economies came together to determine how to best
assure the quality and integrity of human clinical research and thereby ensure
that the results of such research can be recognized by regulatory authorities
across the region.
This APEC-sponsored workshop was particularly timely given the very rapid
growth of clinical research in Asia and South America, with both economic and
public health implications for ensuring high quality.
"From a strategic standpoint, two regions that the United States wants to
work with most closely, Asia-Pacific and South America are both part of APEC. So
APEC is a very good forum for organizing this program," said Dr. Lepay who has
conducted similar training throughout Western and Eastern Europe, Latin America,
Asia, and the Middle East.
Recognizing the ICH as an international platform for good clinical practices,
member economies explored how to adapt these standards in an effort to harmonize
their own practices.
Thailand's Secretary General for the Food and Drug Administration, Dr. Chatri
Bangchuin, said "The objective of this program is to ensure the region's safety
and to promote good clinical trials."
Added lead instructor, Dr. David Lepay, "We hope to build skills that are
fundamental to inspecting. These skills include audit planning, informed consent
review, data auditing, interviewing techniques and site examinations." He added,
"Each of these components is akin to understanding the steps in building a
house."
Clinical research ethics are an important component of GCP training; so the
workshop included a discussion of the regulator's role in the informed consent
process, the operation and inspection of ethics committees, the oversight
responsibilities of the research institution, and culminated in a site visit to
a clinical research center in Bangkok.
"As a result of this workshop, I have been able to realize that there are
spaces in which we as the regulatory authority must provide information about
how to select a site and how to carry out all that is related to the research.
The information will help to facilitate the decisions taken by the
pharmaceutical companies and the research of a patient. I go back to Chile with
new tasks and new areas for investigation," said Mr. Guerra Gonzalez.
At the site visit to the Thai Red Cross AIDS Research Center, the workshop
participants had the opportunity to discuss study conduct as well as ethical
issues related to a clinical trial for HIV-infected children.
"As regulators, we want to make sure that ethics boards consider all the
important ethical issues," advised Dr. Lepay. "Participants found how difficult
it is to sometimes identify the required elements of informed consent. And with
the increasing globalization of clinical trials, there are issues of language
and culture to consider beyond just the technical aspects of GCP."
The site-visit host had a different perspective but still gained a valuable
lesson from visiting representatives of APEC's international regulatory
community.
PREDICT
project leader, Dr. Thanyawee Puthnakit, who is a pediatrician with the Thai Red
Cross AIDS Research Center declared that the study team became more aware about
the process of FDA inspection and what regulatory authorities are looking for.
"We learned about each individual economy's concerns. I think that for the
participants for each regulatory environment, it's good for them to learn about
the GCP standards and to learn about the regulatory environment for a specific
economy in order for them to understand how to conduct inspections," Dr.
Puthnakit concluded.
Benefits to the region
Some call APEC a talk shop. And while that's true at many levels it shouldn't
be interpreted as a negative critique. APEC provides a platform for the region's
officials to share information in a non-threatening environment - and that's
important for regional diplomacy, especially when frank discussion is necessary
for building regional capacity.
Whether senior officials are discussing policy that concerns regional
integration or at the working level, regulators share information about
developing standard operating procedures to help to harmonize standards to make
it easier for companies to invest and sell their products in foreign markets.
Attracting companies to conduct new drug studies is still lucrative. For some
economies, these studies help create good paying, high technology jobs.
Evidence-based clinical studies help regulators to assure the safety and
efficacy of marketed drugs and optimize conditions of their use for the local
populations. It also means that patients will have quicker access to these
drugs, thus improving an economy's collective health.
"While we have come a long way in developing our Good Clinical Practices,
this workshop provides us with a good opportunity to share information with our
peers to help bring them up to a standard that would increase their
competitiveness," said Joyce Wang who serves as the Bureau of Pharmaceutical
Affairs' Section Chief at Chinese Taipei's Department of Health.
"Providing best practices to our colleagues in other economies will raise the
quality of drugs, speed approval processes and bring more drugs to market and
more quickly address patients' needs."
It's important to note that multinational corporations are not the only
beneficiaries.
"Thailand has some clinical trials that are conducted through universities
and institutions," said Ms. Wapeewuttikorn.
"We can increase awareness of GCP among research groups focusing on herbal
products and traditional medicine. We can inspect any clinical trial, not only
those of multinational companies. By working with small and medium-sized
enterprises we encourage their competitiveness," she added.
In the end, consumers benefit as a result of good clinical practice
inspections: data credibility is more sound and patients' rights and safety are
protected.
