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Pushing the Regulatory Agenda on Adult Stem Cells

María Pascual (Courtesy, María Pascual/Cellerix)

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.

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

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

(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.

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