Harmonizing Regulatory Practices Across APEC: Good Clinical Research Inspection Global pharma necessitates harmonized regulation
Multinational drug companies conduct clinical research and trials in many countries and market the resulting products around the world. And in each country the companies face a different regulatory environment.
Importantly for APEC, clinical research has grown rapidly in Asia and South America.
"Companies found many economic reasons for this expansion including active encouragement by many governments," notes Dr. David Lepay, the U.S. Food and Drug Administration's Senior Advisor for Clinical Science.
Attracting companies to conduct drug studies is lucrative. It creates well-paid high technology jobs, can result in new products for manufacture and export, and can spawn support industries. It also means that a country's population gets quicker access to new drugs, thus improving the economy's collective health.
Dr Lepay explains the shift. "Clinical trials could also be accepted by the United States Food and Drug Administration 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.
"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."
To counter this perception and to protect the rights and safety of their populations, APEC member economies have been anxious to develop harmonized regulatory practices for clinical research. Similarly, pharmaceutical companies recognize that for the industry to prosper their research must be seen to be clinically rigorous and ethical.
International standards were first set for developed countries at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in the 1990s. The ICH sets out Good Clinical Practice (GCP) standards that reflect globally accepted ethical and quality principles.
These principles have now been incorporated into the laws and regulations of 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 from the Chilean Institute of Public Health.
The Challenge
While laws and regulations for GCP are important first steps, the implementation of these laws, through regulatory oversight and inspection, is a critical and continuing challenge.
Within APEC the levels of implementation vary from one member to another, regulatory budgets are often limited and inspection infrastructures have not yet been universally built.
For example, Indonesia has legislation in place, training has been provided, and inspections are underway. By contrast, although the Philippines has started conducting GCP inspections they are still setting up a regulatory framework.
"In the absence of our own official guidelines or standard operating procedures on Good Clinical Practice, we currently adopt international standards like the ICH Harmonized Tripartite Guidelines 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 confined only 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, standard operating procedure and GCP, is largely delegated to the [trial] sponsor."
Even when a sophisticated regulatory infrastructure is in place there can be problems. As Dr Lepay explains, "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."
APEC Response: Capacity Building for the Region's Drug Regulatory Authorities
Seeing a need for building the technical skills of the Asia-Pacific region's regulators, Thailand's Food and Drug Administration (FDA) proposed an APEC project aimed at capacity building for regulatory agencies on clinical trials and good clinical practice.
To this end a workshop focused on training regulators in GCP and clinical research inspection was held in Bangkok in May. It brought together staff from the U.S. FDA, the leading global experts in GCP, with medical regulators from many other APEC member economies.
"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.
"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," outlined Dr Lepay. "Each of these components is akin to understanding the steps in building a house."
The importance of the workshop for Thailand was explained by Ms. Akanid Wapeewuttikorn of Thailand's FDA, a project coordinator. "The law will indicate broad policy but this workshop can help us develop the standard operating procedure templates for regulators and inspectors.
"This workshop actually 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."
Dr. Yuppadee Javroonget, head of Thailand's FDA international affairs pision, explained, "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."
"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," she said.
"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," said Mr. Gonzalez Guerra. "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."
The Philippines' Bureau of Food and Drugs would like to make changes.
"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," said Mr. Asprec.
The workshop also brought talk of GCP from the realm of theory into the realm of practice. 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 the Thai Red Cross AIDS Research Center in Bangkok.
At the 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."
Benefits to the region
The benefits of information sharing and skill building in relation to clinical regulatory practices are widespread.
"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. Benefits flow to the public sector and SMEs too.
"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.
Consequently, these activities make it easier for pharmaceutical companies to invest and sell their products in foreign markets; increase the output of economies; help ensure patients' safety and rights are better protected; and lead to improvements in the health of the region's population.
Ultimately, these outcomes reflect APEC's singular role in the region.
APEC's unique mix of industrialized and developing economies provides a forum for dealing with issues, such as the harmonization of clinical regulatory practices.
Moreover, APEC uniquely 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.