what countries does the u.s. send clinical trials to
Perspect Clin Res. 2016 Apr-Jun; vii(2): 62–67.
Multi-regional clinical trials and global drug development
Premnath Shenoy
Quality and Regulatory, DSSPL, Bengaluru, Karnataka, India
Abstract
Drug evolution has been globalized, and multi-regional clinical trial (MRCT) for regulatory submission has widely been conducted by many discovery based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets and meliorate patient access to new and innovative treatments. Sponsors are facing several challenges while conducting multiregional clinical trials. Challenges under the heads statistics, clinical, regulatory operational, and ethics have been discussed. Regulators in different countries such every bit USA, EU-Japan, and People's republic of china have issued guidance documents in respect of MRCT'southward. Lack of harmonization in the pattern and planning of MRCT is perceived to create a difficult situation to sponsors adversely affecting progressing MRCT in more and more discoveries. International briefing on hormonisation (ICH) has initiated the process for having a harmonized guidance document on MRCT. This document is likely to exist issued in early 2017.
Keywords: Clinical trials, international conference on harmonization, multi-regional, United States of America Food and Drug Administration
INTRODUCTION
Condom and efficacy information generated from local patients are a regulatory requirement in many countries including key markets such equally USA, EU in the W, and China, Republic of india, Japan, Korea in the East.
The drug lag problem in several countries can exist attributed to multiple causes; the two major beingness sluggish or no drug innovation and the suboptimal regulatory environment around the clinical trial and drug approving processes.
Drug development has been globalized and multi-regional clinical trial (MRCT) for regulatory submission has widely been conducted by many discovery based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets and improve patient access to new and innovative treatments. Clinical trials beyond multiple regions of the world have go common practice, with the ultimate goal to bring good medicinal products to patients effectually the globe, every bit fast as scientifically possible.
In recent years, information from MRCTs have been submitted to multiple regulatory agencies in international conference on harmonization (ICH) and non-ICH regions. Regulatory agencies are currently facing some challenges in evaluating data from MRCTs for drug approving.
To ameliorate understand the nature and extent of industry experience and the approaches to MRCTs, the Pharmaceutical Inquiry and Manufacturers Clan of America (PhRMA) MRCT Key issue team piece of work-stream surveyed PhRMA member companies on a number of areas relevant to phase 3 registration MRCTs.[1] Survey results supported the apparent industry trend that a big number of companies have decided to conduct trials in a new region over the last decade, with a significant majority of those going to new regions to conduct late phase or postmarketing trials. In that location seems to be an increasing motility to Asia, Latin America, the Middle Eastward, and Africa, where the clinical trial environments are not as mature as in N America and Western Europe. The results support the often-heard claim that local medical practice and standards of care can exist very unlike amid the regions yet can be successfully navigated. The report elaborates on the touch on of conducting MRCTs on sponsors, including changes to regulatory functions and staffing models of those companies expanding their achieve.
ICH E5 guideline[2] was adopted in 1998 (updated in 2006) with the purpose to facilitate the registration of medicinal products among dissimilar geographic regions by recommending a framework for evaluating the affect of ethnic factors upon the efficacy or condom of a product.
BENEFITS
MRCTs can expedite global clinical development and facilitate registration in all regions across the globe. The ultimate goal of MRCT is to bring new medicines to patients globally as fast equally scientifically possible and reduce the drug lag. MRCT also helps in expansion of clinical inquiry into developing countries bringing medical care options to subjects who otherwise may not take access to them. Investment in drug development increases potential benefits to local scientific and medical and paramedical professionals. It provides access to more advanced technologies and helps in the evolution of technical expertise. MRCT provides the sponsors access to otherwise untapped pools of patients, besides as early patient admission to new medications.
REGULATORY GUIDANCE
On one paw, there has been conflicting opinions from several regulatory bodies while reviewing the data from MRCT of New Drug Applications (NDAs). On the other, stringent approval for clinical trials and extended review periods pose big challenges to global pharmaceutical companies in many markets including cardinal countries while conducting MRCT.
Guidance relating to MRCTs from regulatory health authorities is growing, where some bodies position their region in the context of an MRCT, whereas others identify an emphasis on their ain region, e.g. "basic principles on global clinical trials."
Pharmaceuticals and Medical Devices Agency[3] in Japan has made concerted efforts to change the situation so that more than and more MRCTs are conducted in Nippon and drug lag is reduced.
European medicines agency (EMEA)[4] has published a reflection paper on the extrapolation of results from clinical studies conducted outside of the Eu to the Eu population. This reflection newspaper highlights examples of mainly extrinsic, but also intrinsic factors that may complicate the extrapolation of results from clinical studies between geographical areas worldwide every bit well as within the EU population. Concerning medical practise, one of the factors that tin complicate the interpretation of the validity of the results in dissimilar geographic areas is differences in comedications and invasive procedures. Particularly in studies on weather that crave intensive medical intendance, the standard of care can take an important impact on the result parameters. Transferability of the results of these studies might be dumb.
EMEA opined that because that more clinical trials are performed in new regions in which social and cultural aspects may exist different in comparing to the EU population; the influence of extrinsic factors could be of detail involvement. However, intrinsic factors are also of high importance, as specified in the ICH E5-guideline.
Us Food and Drug Administration (FDA)[five] has provided its reflection on Regulatory and Scientific Issues Regarding Use of Foreign Information in Support of NDAs in the USA. The fundamental considerations recommended past USFDA includes the potential heterogeneity in treatment effect across regions may need to be considered in the designing and sizing of MRCTs, using a quality-by-design approach, in which quality is built into the scientific and operational pattern of a trial. Trial quality ultimately rests on having a well-articulated investigational plan with clearly defined objectives and associated outcome measures together with investigators who bear out the study as planned. USFDA has reiterated that the likelihood of a successful trial can be dramatically improved through prospective attention to preventing important errors that could undermine the ability to obtain meaningful information from a trial. USFDA has also suggested improvement in the oversight of MRCT's and comeback in statistical assay plans that specifically address the features of MRCTs.
The Chinese FDA issued guidance on international multi-center clinical trials of drugs in China on January xxx, 2015, which began implementation on March 1, 2015.[six] Now, the Chinese FDA expects to encounter overseas and multinational pharmaceutical companies conducting international multi-center clinical trials of drugs in China. The Chinese guidance stipulates that for those International multi-centre clinical trial data used for application of drug registration in China, must at least involve two countries, including People's republic of china, and should refer the requirements of this guidance. The guidance includes following additional requirements:
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The overseas applicant must conduct a holistic evaluation of the global clinical trial information gear up and a trending analysis of the information from trial subjects in Asia and China. When analyzing the Chinese clinical trial data, specifically, the overseas applicant should evaluate whether the enrolled Chinese trial subjects are representative of the relevant patient population in Chinese medical practise
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The overseas bidder must ascertain whether the Chinese trial subject sample size sufficiently supports the conclusion that the trial drug is rubber and effective for Chinese patients, and whether the Chinese trial subject sample size meets the statistical requirements and the relevant laws and regulations' requirements
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The overseas bidder must attach to internationally accepted Good Clinical Practice (GCP) principles and ethical standards. They must also allow the Chinese FDA to inspect the trial sites from time to fourth dimension, which tin can be any of the onshore or offshore sites involved in the international multi-middle clinical trials.
The touch of different regulatory requirements for Trial endpoints in MRCTs is another outcome faced by the sponsors. Harmonized guidance would be the path to more efficient MRCTs.
Lack of harmonization in the design and planning of MRCT is perceived to create a hard situation to sponsors adversely affecting progressing MRCT in more than and more discoveries.
Issues in planning MRCTs include usefulness of MRCTs in drug developments, essential points for conducting MRCTs (GCP, etc.), importance of ethnic factors evaluation on drug efficacy/safety in MRCTs, etc., Problems in designing MRCTs, points to consider in dose determination for MRCT (exploratory and confirmatory),
how to control various concomitant medications in each country, consideration on definition of a population and methods of sample size interpretation for a population/region, etc., and encouraging a parallel scientific consultation with multiple regulatory agencies in advance.
To address the challenges faced by Regulatory agencies and promote conducting MRCT by sponsors, a harmonized international guideline especially focusing on scientific problems in planning, designing MRCTs, International conference on harmonization (ICH) has initiated developing ICH E17.[7] This new guideline volition complement the guidance on MRCTs provided in ICH E5 (R1)[i] and facilitate MRCT information acceptance past multiple regulatory agencies. Consequently an ICH Proficient Working Group (EWG) has been established and mandated to typhoon an ICH guideline on general principles on planning/designing MRCTs. The EWG consists of ii or three members nominated by European union, EFPIA, FDA, PhRMA, MHLW, JPMA, Health Canada, and Swiss medic. One fellow member is also be nominated by the WHO observer and Drug Regulatory Government and Section of Wellness. It is expected that the document will come for public consultation by the terminate of 2015 or early 2016.
CHALLENGES AND ISSUES
MRCTs take benefits but likewise come with a ready of challenges.
There have been several issues faced by various stakeholders in the conduct of MRCT over the last decade. Concerns were mentioned in a systematic review of controlled trials published in 1998.[eight]
Private companies have come out with position papers, for case, Pfizer has placed a position newspaper on its website addressing reasons why clinical trials are and should be done globally, including the developing earth.[9]
Tsou et al.[10] have described issues related to design and assay of the study with the objective to satisfy unlike regional requirements on principal endpoints.
The USA Department of Health and Homo Services, the part of the inspector general, issued a report, challenges to FDA'south Power to Monitor and Inspect Foreign Clinical Trials.[xi] This report investigated both the extent to which sponsors submitted data from trials outside the USA to support drug and biologic marketing applications approved by FDA in the financial yr, 2008, and also investigated the extent to which FDA monitors and inspects foreign clinical trials that support marketing applications.
International health authorities and authorities-sponsored efforts accept provided some guidance[2,12,13,fourteen] but there is a lack of harmonized guidance from health authorities.
Issues faced in MRCT'southward can be classified into 5 broad categories viz., statistical, clinical, operational, regulatory and ethical.
Statistical issues may include factors such as the importance of predefining the definition of the region, the impact of regional differences on power interpretation/sample size, methods for subgroup assay, randomization bug, how to draw and present information by region and so on.
Clinical factors include extrinsic versus intrinsic factors, lack of quality data showing the comparability of pharmacokinetic/pharmacodynamic relationships amidst different ethnic/racial groups, or among "regions," differences in standard of care with markedly varied medical exercise, including disease definitions, differences in admission to the regional healthcare system, differences in criteria for hospitalization and treatment, concomitant medications, differences in diet, smoking, booze, placebo responses, cultural differences, adverse event reporting, and evaluation and endpoints.
Operational issues could include challenges when moving from phase II to stage III to postmarketing (eastward.thou., expanding number of sites, regions, standard operating procedures (SOPs) and manuals, including global clinical SOPs, information handling SOPs, operational SOPs (translations, training), technological standards/telecommunication bandwidth, multi-regional trial versus multiple regional trials, enrollment, access to the appropriate patient population, drug supply, IVRS, randomization, trial quality and integrity, investigator training, quality balls (QA), data management, and data quality, plan in the protocol for sources of heterogeneity accommodate the sample size equally needed, how do we measure quality and integrity? Is QA separate from quality command (QC), e.thousand., the QA audits of the QC activities to ensure compliance to GCP, company policies, etc.,
Regulatory matters include dealing with differing (and possibly opposing) regulatory requirements, including differing chief and secondary endpoint requirements, divergence in the requirements for the control arm, in clinical studies European union verses United states of america verses Asia, obtaining agreement from differing wellness regime. The level of evidence needed, based on the studies and based on the health authority resource (reliance on other health authorities). Regulatory bug also include handling dissimilar regulatory review and approving times when trying to orchestrate a simultaneous global submission, managing, and responding to requests across multiple agencies, determining the acceptability of MRCT data.
Upstanding problems include adequacy of protection of enquiry subjects, informed consent, integrity of research bear, ease of access, transparency of the research, quality of the review that permits the conduct of the research, local Ethics Committees, Institutional Review Board's, etc. data collection/privacy, need to behave an MRCT co-ordinate to GCP standards, relevant country and local statutes regarding Ethical Committee reviews, informed consent, withdrawn consent, protection of human being patients participating in biomedical research.
Determination
A high level of country-contained harmonization is needed to facilitate sponsors in the acquit MRCTs. This harmonized guidance should ensure a common agreement and approach to clinical trial procedures, patient management, cess, and reporting. The minimum acceptable benchmark for running a clinical trial anywhere in the world needs to be established.
Regulatory agencies in Nippon have taken measures to encourage MRCT to improve patient access and reduce drug lag. China has also released a guidance document early on this twelvemonth on MRCT. There is a need to define clearly to restrict when protocol amendment may be allowed to be carried out especially if it requested from ane state or several regions.
Some of the key points to be considered for the successful bear of MRCT and deal with various challenges and issues are given in Table 1.
Tabular array 1
Points to exist considered in multi-regional clinical trial'south
If the regulatory environs in People's republic of china and Bharat becomes more conducive in terms of timelines of approval, one large stage Three MRCT written report could suffice to submit NDA in nigh of the leading markets in the earth and reduce the drug lag substantially.
India needs to accept a comprehensive guidance document for MRCT and steer clear of upper age restriction of patients recruited to ensure uniformity in the global study protocol and inclusion/exclusion criteria uniformity and in line with sponsors original proposal and as approved in key countries such every bit U.s. and Eu.
It may be presumed that substantive research work and future feel on critical data QA and important ethical considerations would help shape successful MRCTs for the continued globalization of drug development.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
ane. Binkowitz B, Ibia E. Multiregional clinical trials: An introduction from an industry perspective. Ther Innov Regul Sci. 2011;45:569–73. [Google Scholar]
2. International Briefing on Harmonisation; guidance on ethnic factors in the acceptability of strange clinical data; availability – FDA. Notice. Fed Regist. 1998;63:31790–6. [PubMed] [Google Scholar]
3. Basic Principles on Global Clinical Trials, Notification No. 0928010, September 28thursday, 2007, JPMA (This Document is an Informal Translation by PMDA of the Final Notification Published in Japanese on September 28th, 2007 and is Intended to Utilize as a Reference for Considering Global Clinical Trials. 2007. [Last accessed on 2015 Aug 13]. Bachelor from: https://www.pmda.go.jp/files/000157900.pdf .
4. Reflection Paper on the Extrapolation of Results from Clinical Studies Conducted Outside of the EU to the Eu Population, EMEA/CHMP/EWP/692702/2008. 2009. Oct 22nd, [Last accessed on 2015 Aug thirteen]. Available from: http://world wide web.emea.europa.eu .
5. Khin NA, Yang P, Hung HM, Maung KU, Chen YF, O'Connell M, et al. Regulatory and scientific issues regarding use of strange information in support of new drug applications in the Usa: An FDA perspective. Clin Pharmacol Ther Genomic Med. 2013;94:230–42. [PubMed] [Google Scholar]
6. Latest Regulations on Pharmaceutical International Multi-Centre Clinical Trials in China Access China Direction Consulting Ltd. SKU: ACCH5499504. 2015. Mar nineteen, [Final accessed on 2015 Aug sixteen]. Available from: http://www.marketresearch.com .
7. Final Concept Paper E17: Full general Principle on Planning/Designing Multi-Regional Clinical Trials Dated. 2014. May 21, [Terminal accessed on 2015 Aug 08]. Available from: http://www.ich.org .
8. Vickers A, Goyal Due north, Harland R, Rees R. Exercise certain countries produce simply positive results? A systematic review of controlled trials. Control Clin Trials. 1998;xix:159–66. [PubMed] [Google Scholar]
10. Tsou HH, Tsong Y, Chang WJ, Dong X, Hsiao CF. Blueprint and analysis issues of multiregional clinical trials with dissimilar regional primary endpoints. J Biopharm Stat. 2012;22:1051–ix. [PubMed] [Google Scholar]
11. Department of Health and Human Services, Office of Inspector General. Challenges to FDA's Ability to Monitor and Inspect Strange Clinical Trials. 2010. Jun, [Last accessed on 2015 Aug 18]. Available from: http://world wide web.oig.hhs.gov/oei/reports/oei-01-08-00510.pdf .
13. International Conference on Harmonization, Expert Clinical Practice, ICH GCP E6. [Last accessed on 2015 Aug 15]. Available from: http://world wide web.ichgcp.net .
fourteen. World Health Organization. Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products. Technical Written report Series, No. 850, Annex3. 1995. [Final accessed on 2015 Aug 17]. Available from: http://world wide web.apps.who.int/medicinedocs/pdf/whozip13e/whozip13e.pdf .
Articles from Perspectives in Clinical Research are provided here courtesy of Wolters Kluwer -- Medknow Publications
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840793/
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