RAMB - MAIO 2017

thical

issues

the

“

synthetic

”

phosphoethanolamine

clinical

trial

ssoc

ras

2017; 63(5):388-392

389

declarations and other documents, and were clearly de-

lineated by Emanuel et al.

A first concern about the syn-phospho clinical study

refers to whether its potential benefits for patients and

the knowledge gained by society do in fact outweigh the

risks for participants. One can always say that any clinical

trial of a new drug or therapeutic intervention poses risks

to subjects no matter how many nonclinical tests have

preceded them. Owing to uncertainties regarding extrap-

olation between species and other methodological limita-

tions of toxicity tests, preclinical safety evaluations can

never rule out entirely the risks posed by a new medicine

to patients. Nonetheless, regulators, bioethicists and most

scientists agree that preclinical safety studies can disclose

a number of potentially serious health hazards posed by a

new and previously untested drug.

Therefore, the conclu-

sion that an investigational drug is reasonably safe to be

tested in humans must always stand on the best evaluation

of data from nonclinical in vitro and in vivo studies.

Guidelines for clinical development of new pharma-

ceutical products issued by different regulatory agencies

and international organizations are clear about this

ethical requirement. The guidance by the Council for

International Organizations of Medical Sciences (CIOMS)

and the World Health Organization (CIOMS-WHO), for

instance, states explicitly (comments to guideline 8): “[…]

clinical testing must be preceded by adequate laboratory

or animal experimentation to demonstrate a reasonable

probability of success without undue risk.”

The trial of syn-phospho in cancer patients does not

comply with this ethical requirement because there are

few preclinical studies on this compound and available

data point towards an unfavorable risk-benefit ratio. Not

only did laboratory and animal screening tests fail to

demonstrate a potential anticancer activity, but also syn-

-phospho toxicity profile available at the time of ethical

approval decision and trial onset were clearly insufficient

to support test in humans. Moreover, Conep overlooked

data from two experimental studies suggesting possible

harm to cancer patients.

The first major problem with this clinical trial proto-

col is the poor characterization of the “new” drug under

investigation.

Phosphoethanolamine (NH

OPO

syn phosphorylethanolamine, O-phosporylethanolamine;

CAS Number 1071-23-4; Molecular weight 141.06) is an

intermediate in the synthesis of phospholipids that serve

as components of cell membranes. Within the cells, it is

formed by ethanolamine kinase-mediated phosphoryla-

tion of ethanolamine. This primary amine can also be

synthesized in the laboratory and a highly pure phospho-

ethanolamine (O-phosphoethanolamine ≥ 99.0% pure)

is offered by a commercial supplier (Sigma-Aldrich Prod-

uct Catalog Number # 27640). Phosphoethanolamine,

irrespective of whether its origin is endogenous or exog-

enous, is a single molecule, thus receiving identical Chem-

ical Abstract Service (CAS) Registry number.

Gilberto Chierice and coworkers, however, placed the

adjective “synthetic” before phosphoethanolamine to

label the chemical synthesized at their own laboratory (at

the University of São Paulo, São Carlos campus). In six

articles, Chierice and coworkers reported the effects of

syn-phospho on cytotoxicity and xenograft tumor rodent

assays.

5-10

It is of note that in five of these six studies the

authors did not declare the purity of the test com-

pound,

5-7,9,10

and in one study they informed that syn-

-phospho (analyzed by high-performance liquid chroma-

tography) was 99% pure.

A Nuclear Magnetic Resonance

(NMR) analysis conducted by an independent laboratory

(University of Campinas – Unicamp) contracted by the

Ministry of Science Technology and Innovation (MCTI),

however, found that phosphoethanolamine accounted

for only 32.2% of the so-called “synthetic” phosphoetha-

nolamine.

The remaining constituents were impurities

such as of Ca-, Mg-, Fe-, Mn-, Al-, Zn- and Ba-phosphates

(34.9%), monoethanolamine (18.2%), pyrophosphates

(3.6%) and phosphobisethanolamine (3.9%).

The diver-

sity and amount of impurities in syn-phospho indicate

that its effects on nonclinical and clinical tests may result

from constituents other than phosphoethanolamine, or

even to an interaction between constituents.

In any clinical trial application, regulatory agencies

generally require from investigators and sponsors sufficient

information regarding pharmaceutical quality, or the prop-

er identification, quality, purity and strength of the inves-

tigational drug. The drug’s pharmaceutical quality must

also be uniform and consistent across batches used in

preclinical and clinical studies to ensure that the preclini-

cal safety evaluation and subsequent clinical trials tested

essentially the same investigational drug product. Based

on the results from the MCTI-contracted chemical analy-

sis, syn-phospho is far frommeeting standards of pharma-

ceutical quality required for investigational drugs.

In December 2015, the MCTI contracted a limited

set of preclinical studies of syn-phospho consisting of

in vitro assays (cytotoxicity, and genotoxicity tests) and

in vivo rodent (acute toxicity, mouse bone-marrow mi-

cronucleus test, rodent xenograft tumor test, and 7 and

28 day repeated oral dose test in rats).

These preclinical

studies were still in progress when the Conep approved

the clinical trial protocol and thus it is unclear whether