RES E A R C H Open Access
Capacity for ethical and regulatory review
of herbal trials in developing countries: a
case study of Moringa oleifera research in
HIV-infected patients
Tsitsi G. Monera-Penduka
1*
, Charles C. Maponga
1
, Gene D. Morse
2
and Charles F. B. Nhachi
3
Abstract
Background: Lack of regulatory capacity limits the conduct of ethical and rigorous trials of herbal medicines in
developing countries. Sharing ethical and regulatory experiences of successful herbal trials may accelerate the field
while assuring human subjects protection. The methods and timelines for the ethical and regulatory review
processes for the first drug regulatory authority approved herbal trial in Zimbabwe are described in this report.
Methods: The national drug regulatory authority and ethics committee were engaged for pre-submission discussions.
Six applications were submitted. Application procedures and communications with the various regulatory and ethics
review boards were reviewed. Key issues raised and timelines for communications were summarized.
Results: There was no special framework for the approval of herbal trials. One local institutional review committee
granted an exemption. Key issues raised for revision were around pre-clinical efficacy and safety data, standardization
and quality assurance of the intervention as well as consenting procedures. Approval timelines ranged between eight
and 72 weeks.
Conclusions: In the absence of a defined framework for review of herbal trials, approval processes can be delayed.
Dialogue between researchers and regulators is important for successful and efficient protocol approval for herbal trials
in developing countries.
Trial registration: The study was registered prospectively on August 3, 2011 with clinicaltrials.gov (NCT01410058).
Keywords: Herbal trial, Regulation, Developing countries
Background
Clinical trials are considered the gold standard in terms of
evidence of efficacy and safety of herbal medicine, yet very
few trials are conducted in developing countries. Insuffi-
cient capacity, including establishment of ethical and
regulatory frameworks to support the conduct of herbal
trials are often cited as a contributing factor [1, 2].
Current strategies to enhance capacity of researchers
in developing countries to conduct ethical and rigorous
herbal trials are focused on research training and re-
source mobilization and have not included sharing
experiences involved in successful ethical and regulatory
review processes [2, 3].
Clinical studies of herbal medicines should be de-
signed to produce new, beneficial and generalizable
knowledge that will improve health outcomes while as-
suring human subjects protection. However, difficulties
in determining shared concepts of social value, scientific
validity and favorable risk–benefit ratio, make this chal-
lenging. Nevertheless, herbal medicine researc h must
endeavor to achieve a balance between scientific validity
and ethics [4]. Public dissemination of ethical and regu-
latory processes, issues and challenges by researchers
involved in herbal trials in developing countries will pro-
vide a platform to learn and build capacity for other
researchers. In January 2013, the Zimbabwean national
* Correspondence: moneratg@yahoo.co.uk
1
Drug and Toxicology Information Services (DaTIS), School of Pharmacy,
University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Monera-Penduka et al. Journal of Pharmaceutical Policy and Practice (2017) 10:9
DOI 10.1186/s40545-017-0099-5
drug regulatory authority approved the first trial with a
herbal intervention; the Moringa oleifera supplementa-
tion by patients on antiretroviral therapy (MOART)
study. In this article we describe the ethical and regula-
tory processes that were involved; including the human
subject protection issues raised and the time taken to ac-
quire the requisite approvals. This experience should
stimulate discussion and facilita te the set up of regula-
tory and ethical frameworks to support the conduct of
herbal trials in other developing countries.
Methods
Description of the herbal trial
The MOAR T study was conducted by scientists from the
University of Zimbabwe to determine if antiretroviral drugs
are affected by concurrent intake of Moringa oleifera Lam,
a frequently taken dietary supplement in Zimbabwe. This is
important because herbal medicines may interact with con-
ventional medicine resulting in increased or decreased drug
exposure. The drugs nevirapine and efavirenz were studied.
Both drugs are routinely used as part of combination ther-
apy for treating HIV. The study was an intensive pharma-
cokinetic sampling study which compared pre- and post
Moringa oleifera Lam. plasma concentration profiles of efa-
virenz and nevirapine in HIV -infected people on antiretro-
viral therapy. Moringa was administered as a standardized
dry leaf powder in a one sequence cross-over, open label,
phase I/IIa, observational study that was conducted over
35 days. Venous whole blood and urine were sampled
after a 21-day washout period as well as on day 35
following 14 days of moringa supplementation. Compli-
ance to medication and supplementation restrictions
was assessed through reported adherence, pill count s
and e valuation of a food/herb/medication diary. The
trial is registered w ith clinicaltrials.gov N CT01410058.
Ethical and regulatory framewor k
In Zimbabwe, there are three regulatory bodies involved
in clinical research, namely the Medicines Control Au-
thority of Zimba bwe (MCAZ), the Medical Research
Council of Zimbabwe (MRCZ) and the Research Council
of Zimbabwe (RCZ). MCAZ is the national drug regula-
tory (NDRA) authority which approves and monitors all
clinical trials in Zimbabwe in terms of Part III of the
Medicines and Allied Substances Control Act [Chapter
15:03]. It has a well-established framework encompass-
ing trial approval procedures and conduct guidelines,
reporting standards and access to clinical trial and phar-
macovigillence experts.
Before an application for the conduct of a conventional
trial can be submitted to the NDRA, the protocol needs to
go through ethical review by the ethics committees of the
institutions responsible for the trial (IERC). Thereafter,
parallel submissions to the the national ethics committee
(NEC) and the NDRA may be made. The MRCZ is the
NEC. It was established by the Government of Zimbabwe
Notice No. 225 of 1974 and approves and provides ethical
oversight for all health research.
When the protocol has a foreign co-investigator or
planned bio-specimen shipment outside Zimbabwe, add-
itional review an d approval by the national research
council (NRC) is required. The RCZ is the NRC. It is a
statutory body established by the Research Act [Chapter
10:22] which promotes research in all fields and coordi-
nates foreign/and or foreign funded research. All appli-
cations involving health research made to the NRC must
go through the MRCZ.
The MCAZ, the MRCZ and the RCZ have publicly
available guidelines based on the Declaration of Helsinki,
the Council of International Organizations of the Medical
Sciences (CIOMS) Guidelines as well as the International
Conference on Harmonization for Good Clinical Practice
guidelines.
Herbal protocol review procedures
Attheonset,weengagedtheMCAZandtheMRCZin
pre-submission discussions and established that there was
no special framework for the approval of herbal trials. We
were advised to work within the framework for conven-
tional trials.
Following the conventional trial framework, four ethical
and regulatory approvals were required for the MOART
trial. First, ethical approval was sought from the principal
investigator’s institution. Upon approval by the IERCs, fur-
ther applications were made to the national ethics com-
mittee, followed by the national drug regulatory authority.
Due to unplanned bio-specimen shipment necessitated by
limited capacity for one of the analyses, bio-specimen
shipment approval also had to be sought from the NRC.
During the course of the applications the funding col-
laborators also indicated that their institutions required
the protocol to be submitted to them for ethical review.
Subsequently, two further ethical review applications were
submitted to the institution of the foreign collaborating
funder; as well as the institution of a local collaborating
funder, bringing the total number of ethical and regulatory
review submissions to six. However, the IERC for the local
collaborator granted an exemption for ethics review. The
exemption was based on the fact that another local IERC
(IERC1) had already granted approval and the NEC was
also reviewing the protocol.
The local regulatory and ethics committees re viewed a
draft of the manuscript for accuracy.
Results and discussion
Feedback from the presubmission discussions
During the presubmission discussions the NDRA and
NEC personnel directed the researchers to the complete
Monera-Penduka et al. Journal of Pharmaceutical Policy and Practice (2017) 10:9 Page 2 of 5
set of forms and submissions required for the conven-
tional trial application. Guidance was sought on how to
best adapt our responses to fields on the forms that were
originally intended for conventional trials. Discussions
regarding fields related to the trial (herbal) intervention
as well as existing preliminary data were particularly
useful in marrying our planned approach to that of the
regulators. This improved the efficiency with which the
application package was submitted.
Further information requested to support initial
applications
The researchers were requested to provide additional in-
formation on several aspects by the 5 bodies (Table 1).
Some issues wer e raised as recommendations to improve
understanding of the study documents while others were
required as corrections. The three ethics committees
recommended that more detailed descriptions of study
procedures be given in both the protocol and the
informed consent document. In additio n, the IREC2
required a more detailed plan for adverse events moni-
toring and reporting. Both the requests were straightfor-
ward and constituted standard clarification and detail
issues applicable in any clinical trial protocol. The initial
protocol therefore was not complete and the oversight
of the ethics committee was valuable. The missing
details were all addressed satisfactorily in the first
responses.
In addition, the NDRA, NRC and the IERC2 required
justification and corrections around pre-clinical efficacy
and safety data, standardization and quality assurance of
the intervention as well as consenting procedures. These
requests constitute the more challenging issues around
scientific validity of research, risk-benefit assessments
and informed consent that are commonly cited as core
considerations for herbal trial protocols [4, 5]. Regarding
preclinical data, the issue raised was that there were no
published studies assessing the effect of moringa on efa-
virenz or nevirapine whose positive finding s would typic-
ally inform the need for a human study. In response,
reference was made to two World Health Organization
(WHO) guidelines for research on traditional medicine,
which recommend a rapid response research mechanism
for herbs. The guidelines cite prior voluntary use of
herbal medicines and documented experience of long-
term use without evidence of safety problems as is the
case with Moringa oleifera, as a basis of the risk assess-
ment [6, 7]. Additional preclinical studies assessing the
effect of Moringa on metabolic pathways shared by efa-
virenz and nevirapine with positive findings were also
added to the protocol to augment the safety data.
In the initial application, we had proposed to use a sin-
gle batch of Moringa from the most commonly cited local
supplier to maintain generalizability of the findings. The
NDRA however highlighted the need to use Moringa olei-
fera of verified and reproducible quality and required that
measures be put in place and stated explicitly that
would guarantee the integrity of the inter vention. Pre vi-
ous herbal medicine re views have cited product quality
and standardization as a common challenge, particu-
larly in light of the need to preserve external validity
[4, 8]. At the time of the application, the NDRA did
not regulate herbal medicine and did not cite any specific
quality criteria to address the quality issue. Following the
WHO Guidelines for assessing herbal medicines we
assessed three different batches of moringa from the local
market for microbial contamination and heavy metal con-
tent. Unfortunately, all three failed to meet the WHO cri-
teria [9]. We then proposed an alternative approach which
involved processing a batch of moringa leaf powder using
good manufacturing practice (GMP) principles specifically
for the trial, which would then be externally assessed for
quality before proceeding with the trial. This was accept-
able to the NDR A. The batch was subsequently processed
by the School of Pharmacy and externally assessed for mi-
crobial and heavy metal contamination in the Depart-
ments of Biological Sciences and Chemistry laboratories
respectively.
At the time of protocol approval all analy sis was
planned locally and as a result the consent form did not
Table 1 Further information requested to support initial applications
Domain IERC 1 IERC 2 NDRA NEC NRC
Details of research procedures X X X X
Details of informed/storage consent X X X
Reimbursement x x
Details of research design X X
Pre-clinical data to justify human studies X
Details of adverse event monitoring X
Details of product standardization and quality X X
Adequacy of clinical trial site infrastructure X
Re-consenting of participants for specimen shipment X
Monera-Penduka et al. Journal of Pharmaceutical Policy and Practice (2017) 10:9 Page 3 of 5
cover aspects of specimen shipment. When application
was made to the NRC for bio specimen shipment ap-
proval, the NEC required additional consent from partic-
ipants with the affected analysis before approval could
be granted. This was done through targeted contact at
routine HIV clinic visits and support group meetings.
Divergent requirements
The IERC2 required the use of their ‘standard statement
for reimbursement’ for consent which stated that, “In the
unlikely event that you become ill or injured as a direct re-
sult of participating in this study, you understand that you
may receive medical care, but it will not be free of charge
even if the injury is a direct result of my participation”.
This request was not necessarily unique to herbal trials
but comes up often in collaborative trials. It becomes
important to discuss in this context because many herbal
trials in developing countries will be collaborative with
developed countries coming in as the funders [10].
While the statement was consistent with consent doc-
uments for other studies conducted in the United States
of America [11], it was not compliant with the Helsinki
declaration and CIOMS. It was also not in line with the
NEC recommendation, which states “In the event of
injury resulting from your participation in this study,
treatment shall be offered by the study”. Globally, there
is no consensus on the issue of compensation for re-
search related injuries [12]. One school of thought says
that because a participant has accepted that there may
be risks and harms that can occur as a part of the study,
they should not be compensated in case of an injury
[13]. The other says that the con sent process cannot be
extrapolated to argue that the participant also consents
to be harmed during the trial, as risk and harm are often
unknown and unexp ected and should be compensated
[13, 14]. In response we highlighted the differences in
health insurance frameworks in the local context that
made the NEC require free medical treatment or partici-
pant insurance for all research participants. In addition, we
highlighted that the requirements of the ethics committee
ofthestudysettingshouldtakeprecedenceoverthefor-
eign collaborator ones. The response was acceptable to the
IERC2. In fact, current versions of their ‘standard state-
ment for reimbursement’ now incorporate some exemp-
tions for covering costs for research-related injurues. Our
experience supports previous publications that have rec-
ommended democratic deliberations between researchers
and regulators to resolve challenges in herbal medicine
research [4].
Approval timelines
Figure 1 shows the distribution of the time taken to get
approval between researchers and reviewers. The data
incorporates weekends and public holidays.
Delay in ethical and regulatory approval extends the
duration of a trial, thereby increasing its cost and poten-
tially risk losing relevance. This often causes tension be-
tween researchers and ethics committees [15]. The NEC
review had the shortest review committee turnaround
time. Ethics committee turnaround time is usually impli-
cated in protocol approval delays [15]; contrary to the
current experience in the NEC time was shorter that the
respective researcher time. This could be attributed to it
being the only committee that had published turnaround
times for review of applications, indicating that they
have put some thought and effort into imp roving their
efficiency.
The deliberations with the NDRA however took over a
year. The NDRA had the responsibility to thoroughly assess
existing evidence and quality assurance. The apparent delay
mayhavethereforehaveimprovedtheprotectionofpartici-
pants. Delays in meeting review timelines maybe justified
complex protocols where there is need to study the applica-
tion in-depth, or to get additional essential information
from the applicant and to avoid unjustified risks. The distri-
butionintheresponsetimebetween the researchers and
the regulators was 59:41% indicating that the issues raised
demanded significant processing time from both reviewers
and researchers. For instance, the issue of guaranteeing
product quality required assessing several possible options
before reverting to the NDRA. This mirrors the current
global debate on the complex regulation issues associated
with trials of herbal medicines [4, 8].
At the end of 2016, the Ministry of Health and Child
Care in Zimbabwe set up a Complementary and Trad-
itional Medicine Research Committee that would going
forward, sit to review traditional medicine research includ-
ing clinical trials. The move will go long way to promote
successful and efficient protocol approval for future herbal
trials in Zimbabwe.
Some time was also lost due to slow administrative pro-
cedures such as delays in delivery responses of interim
communications or notification of researchers to collect
the same. The results should be interpreted in light of the
limitation that the data is from one study, being the only
clinical trial of a herbal medicine approved by the NDRA.
0 8 16 24 32 40 48 56 64 72
IERC 1
IERC 2
NEC
NDRA
NRC
Approval time/weeks
Reviewer
Researche
r
Fig. 1 Time taken to obtain approvals. The black bars represent the time
taken by the reviewer, while the grey bars represent the researcher’s
response time
Monera-Penduka et al. Journal of Pharmaceutical Policy and Practice (2017) 10:9 Page 4 of 5
Recommendations
There is a need to develop some guidance for the ethical
and regulatory review of clinical trials with herbal inter-
ventions. The WHO guidelines on research on traditional
medicine could be used as a reference to develop an
adapted national regulation. This is particularly important
for aspects of clinical trials that differ between “modern”
and “traditional” medicines, such as pre-clinical data,
standardization and quality assurance of the intervention.
Pre-submission discussions to clarify correct applica-
tion procedures and identification of key areas can facili-
tate efficient and successful reviews.
Open and transparent engagement between researchers,
ethics committees and regulators during the application
process can facilitate resolution of ethical challenges in
herbal trial protocols. This is applicable to deliberations
between researchers and local as well as international
regulators.
Publication of target turn around times for the different
type of applications is a strategy that could be employed
by other regulatory and ethics review bodies to monitor
their efficiency and assist with researchers planning.
Conclusion
As far a s can be a scertained, this report is the first to
describe the ethical and regulatory a pproval processes
of setting up a herbal clinical trial in a developing
country. The experiences highlight the importance of
dialogue between researchers and regulators for suc-
cessful and efficient protocol approval for herbal trials
in developing countries.
Abbreviations
IERC: Institutional ethics review committee; IERC1: Local institutional ethics
review committee; IERC2: Foreign collaborating institutional ethics review
committee; MCAZ: Medicines Control Authority of Zimbabwe;
MOART: Moringa oleifera supplementation by patients on antiretroviral
therapy; MRCZ: Medical Research Council of Zimbabwe; NDRA: National drug
regulatory authority; NEC: National ethics committee; NRC: National research
council; RCZ: Research Council of Zimbabwe; WHO: World Health
Organization
Acknowledgements
The authors thank Alan Wolfe who provided insight that greatly assisted the
research.
Funding
This publication was made possible by grant numbers 2U2RTW007367 and
D43TW007991-01A2 from the Office of Global AIDS Coordinator and the U. S.
Department of Health and Human Services, (National Institutes of Health
(Fogarty International Centre). The two agencies funded the data collection.
Its contents are solely the responsibility of the authors and do not necessarily
represent the official views of the government.
Availability of data and materials
All data generated and analysed during this study are included in this
published article.
Authors’ contributions
TM was responsible for the conception of the study, its design, data
collection, drafting of the manuscript and analysis of data. CN assisted in the
design of the study, supervised the work, contributed to the analysis of data,
revised the draft critically and gave final approval of the version to be
published. GM contributed to the design of the study, the analysis of data,
revised the draft critically and gave final approval of the version to be
published. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
The study was approved by the Joint Research Ethics Committee of the
University of Zimbabwe and Parirenyatwa Group of Hospital as well as the
Medical Research Council of Zimbabwe.
Author details
1
Drug and Toxicology Information Services (DaTIS), School of Pharmacy,
University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.
2
Center for Integrated Global Biomedical Sciences, University at Buffalo,
Buffalo, New York, USA.
3
Department of Clinical Pharmacology, University of
Zimbabwe College of Health Sciences, Harare, Zimbabwe.
Received: 22 October 2016 Accepted: 10 February 2017
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