Pushing the Regulatory Agenda on Adult Stem Cells - From Science Careers

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http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2009_09_18/caredit.a0900113

Pushing the Regulatory Agenda on Adult Stem Cells

By Elisabeth Pain

September 18, 2009

Pascual's job was not to comply with complex regulations--the job of
most regulatory affairs directors--but to help establish them.

In 2006, as the phase II clinical trial showing the efficacy of her
company's product concluded, María Pascual yearned to tell the medical
world about the results. The company, Madrid-based biopharmaceutical
start-up Cellerix, had used adult stem cells from fat tissue to heal
fistulas in patients who had few alternatives to the therapy. The
company, too, was keen to see the work published.

However, the medical world was not entirely ready for the company's
results. Cellerix presented its data during the 2007 Digestive Disease
Week international congress in Washington, D.C. But the data were
turned down for publication by some medical journals. The paper's
referees "had no objections on the clinical trial, on the methodology,
and the results," says Pascual, who was the last author and is the
director of regulatory affairs at Cellerix. Scientifically, everything
seemed fine, Pascual says. But the paper was rejected because the
research "was so new that it could really change the pattern of how to
treat patients, how to understand the disease," Pascual says. The
journals' editors thought it was too soon to alert doctors and
patients.

The regulatory world wasn't ready either. Pan-European standards and
regulations for the development and marketing of advanced therapies--
therapies based on genes, cells, and tissues--were established only in
November 2007 and implemented less than a year ago.

Earlier this year, Pascual saw those results published, in a specialty
journal. With the results of the phase III clinical trials soon to
come out, Pascual expects a warmer welcome. The world, she thinks, is
ready now.

Being ahead of her time is a feeling that Pascual, 34, has gotten used
to. Six years ago, she left a promising career in academia because she
aimed to help industry develop new drugs, stepping into a role she
wasn't prepared for in a world that wasn't yet ready for the work that
she, and her company, would be doing. "It was risky," Pascual says,
"but I had that feeling that I could really reinvent myself around the
stem cells." She has thrived.
A promising academic start

As a Ph.D. student, Pascual's curriculum vitae was typical of someone
you would expect to succeed in academic research. After obtaining a
B.Sc. degree from the University of Granada in her native Spain,
Pascual won a 4-year fellowship from the national science ministry to
do a Ph.D. at the nearby CSIC López-Neyra Institute of Parasitology
and Biomedicine. Under the supervision of immunogeneticist Javier
Martín, Pascual identified genetic markers predicting susceptibility,
prognosis severity, and response to treatment for rheumatoid
arthritis. "The whole aim was to help physicians ... decide who
[should] be treated, when ... , with what medications, and also to
help [companies] develop new drugs," Pascual says.

With the help of her supervisor, Pascual established a collaboration
with researchers at the Department of Immunohaematology and Blood Bank
at the Leiden University Medical Centre in the Netherlands. She spent
several months there during each of 2 years, using the latest
genotyping technologies. During the final year of her Ph.D., she went
to the Mayo Clinic in Rochester, Minnesota, for another 4 months to
expand her research into functional studies. She wanted to understand
why some people are more susceptible than others to disease, or more
responsive to treatment, she says.

"I was really fully focused and just loved it," Pascual says about her
graduate school experiences. By the time she finished her Ph.D. in
2002, Pascual had published 16 papers, most of them as first author,
and received several awards, including the Julia Bodmer Award from the
European Federation for Immunogenetics, given annually to the best
young scientist in that field. "Her scientific production during her
Ph.D. was simply incredible," Mario Delgado, a neuroimmunologist at
López-Neyra Institute of Parasitology and Biomedicine, writes in an e-
mail to Science Careers. Pascual's "doctoral thesis was one of the
best ones I have evaluated."

Yet despite her accomplishments, when she finished her Ph.D. Pascual
knew she was finished with academic research. She felt she had already
had "an intensive research career," she says. During her time at the
Mayo Clinic, she had been exposed to work in industry and come to see
drug development as the natural next step. "So I thought, 'Now I would
like to live this part of real clinical development.' "
A big jump
María Pascual in the lab

(Courtesy, María Pascual)

María Pascual in the lab, as a graduate student

While looking for industry opportunities in Madrid, Pascual heard
about Genetrix, a biotech-company incubator that had recently been
founded by the Spanish National Center of Biotechnology. Genetrix was
looking for research it could develop into new companies.

Genetrix was also looking for a director of clinical development, and
Pascual was hired in 2003. "Initially, I thought it was a mistake,
given that she was quite promising as a scientist," says Delgado, who
had offered Pascual a position as a postdoc in his lab. "At the same
time, I knew ... that she was going to do this industry job well."

Pascual's move from academia to industry was a "big jump," writes
Jorge Alemany, the vice-president for strategy and corporate
development at Genetrix's spinoff Cellerix, in an e-mail. She had to
take responsibility for an important area that she had no experience
in, he adds. "Her initial work was to organize all the issues related
to future clinical development programs."

Because Genetrix was small, Pascual took on a range of tasks. She
started by helping to evaluate the commercial potential of various
bits of science to select those that should be moved into human
testing. The job required "really getting into the science and meeting
the scientists to understand the project and to go to the labs and see
the experiments," she says. Alemany says, "The capacity and
flexibility of María to adapt to different environments and roles ...
is remarkable."

Pascual soon "got in love" with adult stem cells technologies. She
also got involved in the management of the organization, and she
sought a master's degree in Clinical Development and Regulatory
Affairs at the Universitat Autònoma de Barcelona, which she obtained
in 2004. She helped Genetrix launch the company Cellerix, which is
dedicated to the development of adult stem cells therapies. Her job
there was to obtain all the authorizations from the Spanish Agency of
Medicine and Health Products needed both to run a Good Manufacturing
Practices facility and to initiate clinical trials for adult stem cell
therapies.
Leading by example

In 2005, Pascual left Genetrix to become the director of regulatory
affairs at Cellerix. In those days, in Europe, adult stem cells had
demonstrated their potential mostly in academic laboratories and not
yet in commercial settings. The pan-European regulations for
developing and marketing human stem cell products did not yet exist.
European stem-cell companies were stepping into a no-man's land.

Pascual's job was not to comply with complex regulations--the job of
most regulatory affairs directors--but to help establish them. Adult
stem cells represented "a double challenge" from a regulatory point of
view, Pascual says. "It's new, and it's different." The fact that they
are live cells means that most existing development regulations and
procedures for authorization to market didn't fully apply. Pascual
contributed to discussions with the European Commission and the
European Medicines Agency (EMEA) on how to design adequate standards
and procedures for advanced therapies, including adult stem cells.

Things started to improve when cell therapies were classified as
medicinal products for the first time in 2004. But the real step
forward came when, in 2007, the European Commission ruled that all
advanced therapies should go through a centralized authorization
procedure run by EMEA.
Ready for market

Ever since that new legislation was implemented in December 2008, "the
whole field has moved really forward," Pascual says. Established rules
and regulatory pathways made it easier for companies to develop their
products for market and encouraged investors "to believe in the
science" and to spend the money needed to bring products to market,
she says.

The new rules put companies that saw the potential of such therapies,
like Cellerix, in an especially strong position, Pascual says. Pascual
expects to be ready soon to seek marketing authorization for Ontaril
for the treatment of complex fistulas. It would be the first adult
stem cell-based therapy product to reach the market in Europe.

"I don't know how well she would have been doing as a scientist in
academia describing the mutation of such or such protein," says
Delgado, whose lab has collaborated with Cellerix over the years. "But
I believe that she gave much more to science through her role at
Cellerix."

Pascual, too, feels she made good choices. She and her colleagues have
"a lot of good science in our hands every day," she says. "It's very
exciting."

Elisabeth Pain is contributing editor for South Europe.

10.1126/science.caredit.a0900113