NVS Novartis AG

Manipulating data in drug's race to market

By Denise Roland 

This article is being republished as part of our daily reproduction of WSJ.com articles that also appeared in the U.S. print edition of The Wall Street Journal (September 14, 2019).

The startup had something incredible: a cure for babies with a deadly neurological disease. Last year, the company was snapped up by pharmaceutical giant Novartis AG, and by this past May, its drug was the most expensive on the market.

In just a few years, the company, AveXis Inc., morphed from a handful of hospital-based researchers into one of the pharmaceutical industry's most stunning success stories.

But in the hurry to fulfill the drug's promise, AveXis manipulated data that went into the drug's approval, Novartis and the Food and Drug Administration now say.

And some former AveXis employees say there were other stumbling blocks, separate from the manipulation cited by the FDA. They say the company struggled to manage a fast ramp-up of its research and manufacturing operations. They describe a race to develop the drug that, at times, yielded mistakes, including misstated dosing figures from early-stage trials of the drug.

AveXis went through a "fundamental shift in capabilities," a Novartis spokesman said. He said it "evolved from an academic setting to a commercial organization with leaders who had a deeper understanding of the requirements of the pharmaceutical industry and the FDA approval process." The spokesman said new leadership established processes "in line with the needs for a company that was gearing for product approval and commercialization."

In this field, there is plenty of incentive to move fast. Gene therapy -- essentially treating a defective gene with a healthy one -- is one of the hottest areas of pharmaceutical research, sucking in billions of dollars of investment. Early pioneers, under pressure from would-be patients and investors alike, are driven to move quickly from promising research results to the manufacturing of a safe, marketable version of their breakthroughs.

Along the way, these nimble startups can struggle to adapt to the stringent requirements demanded by regulators and the large pharmaceutical companies that typically snap them up. The FDA has encouraged the acceleration, increasingly offering companies fast track approval for promising, lifesaving drugs.

The stakes are high for Novartis, which paid $8.7 billion to buy AveXis. The data manipulation -- which AveXis and Novartis have acknowledged -- occurred before Novartis purchased the company. Novartis later learned of the issue, but didn't alert the FDA while the agency was reviewing the drug. The FDA has opened a criminal probe into the matter, and Chief Executive Vas Narasimhan has struggled to justify his decision to delay disclosure. Novartis has said it wanted to conduct an internal probe before alerting the FDA.

AveXis's drug, called Zolgensma, is one of the first commercially available gene therapies -- and the world's most expensive drug of any kind, at $2.1 million. Many doctors consider it a revolutionary treatment for spinal muscular atrophy, or SMA, a rare but particularly devastating genetic disease in babies. SMA victims lack a gene crucial for muscle control and get progressively weaker, struggling to move, eat or breathe. Untreated, those with the most severe form, known as Type 1, typically die by their second birthday. The FDA has said that the data manipulation issue doesn't change its view that Zolgensma is safe and effective and it has allowed the treatment to stay on the market.

Zolgensma, delivered intravenously in a single dose, promises to halt the disease. The drug's first clinical trial, conducted in 2014 and 2015, treated 15 babies. The first three received a lower dose and the rest a higher dose. All 12 who received the higher dose have passed their second birthday, with most hitting key milestones like holding up their heads, eating by mouth and sitting unaided. So far, there is no sign that the drug's effect decreases over time.

Scientist Brian Kaspar and other researchers at Nationwide Children's Hospital in Columbus, Ohio, had been experimenting with a possible gene-therapy treatment for SMA for years. In 2013, AveXis licensed the technology, eventually bringing on Dr. Kaspar as scientific founder.

The successful early trial generated excitement, just as industrywide interest in gene therapies was rising. The company listed on Nasdaq in 2016. A year later, a video showing the progress of some of the babies in the clinical trial triggered a standing ovation at a packed auditorium during a prestigious neurology conference in Boston.

Working for the Chicago-based company, as it raced to win FDA approval and ramp up commercial-scale production, was both exhilarating and exhausting, according to former employees.

Long hours were the norm, they said. Chief Executive Sean Nolan and Dr. Kaspar regularly reminded employees of the importance of the new gene therapy. "We did [in three years] something that takes most companies 10 years to do," said one former executive.

Some employees say they spotted sloppy practices relating to the early clinical trial. Employees in 2016 found that the calculations done by Dr. Kaspar two years earlier were imprecise, and flagged this to executives, according to a former employee familiar with the matter. Those calculations overstated the dose of the gene therapy that had been given to babies in early-stage trials by a factor of two, this person said.

A Novartis spokesman said AveXis employees discovered the inaccuracy after a shift to a more precise method for calculating the dosing. AveXis corrected those calculations almost four years after they were first carried out, according to a Novartis filing with the FDA last year.

AveXis staff also raised issues about the role of academic labs in the drug's development, according to former employees. In its first clinical trial, staff from Dr. Kaspar's laboratory had conducted blood tests -- used to track the babies' immune responses to the treatment -- at a lab at Nationwide Children's Hospital. That lab wasn't certified to conduct patient testing, former employees say. AveXis later contracted an outside, certified laboratory to conduct tests for subsequent clinical trials, according to these former employees.

A spokesman for Novartis said it wasn't uncommon for this type of test to be performed in an academic laboratory setting "given the emergence of the gene-therapy field at that time." Andrew Wachler, a health-care lawyer, said any lab that performs patient specific tests should be certified.

The scale-up of AveXis "was in many respects quite difficult" for Dr. Kaspar, said a former AveXis executive, adding that Dr. Kaspar sometimes expressed frustration that as the organization grew it became more bureaucratic and decisions took longer.

To win eventual FDA approval, the fledgling company needed to demonstrate it could ramp up commercial production of the treatment. AveXis launched a new manufacturing facility in Libertyville, Ill., near Chicago. The plant needed to run dozens of successive batches of the gene therapy, and provide meticulous documentation.

It was a round-the-clock operation, according to former employees. It wasn't unusual for quality-assurance employees to be hauled out of bed in the middle of the night if a potential issue had arisen with a batch, according to former employees.

A Novartis spokesman said AveXis had a sense of urgency to get the product to children in need. He said that many biotech manufacturing plants work round-the-clock.

To win over the FDA, AveXis had to show the gene therapy made in the company's new factory in Libertyville matched the treatment made and tested at the hospital. To do so, scientists compared how mice with SMA fared with the Libertyville product, versus how they did on the original gene therapy from the hospital.

Those comparisons were done at an AveXis facility in San Diego. They were later submitted as part of the drug's approval application. The FDA signed off on them as satisfactory, according to FDA filings.

But while the FDA was assessing the application, an AveXis whistleblower reported to the AveXis leadership that there was a problem with some of that data. The issue was escalated to Novartis's Chief Executive Vas Narasimhan in early May, but the company didn't alert the FDA until late June, about a month after the drug had won FDA approval and gone on sale.

After Novartis reported the issue, the FDA descended on the San Diego facility where the tests were conducted. Inspectors found a host of problems, according to an FDA report of the inspection. Staff didn't thoroughly review data discrepancies, for instance, and didn't keep satisfactory records. FDA inspectors found a log from August 2018 describing how the lifespans of mice used to test the potency of the drug were recorded differently in different places, according to their report. In the most extreme case, the difference was 19 days. Inspectors went on to say, in the report, that they saw no evidence staff, made aware of the error by quality-control inspectors, made efforts to figure out what happened. Novartis said it has responded to the FDA's concerns.

Novartis replaced Dr. Kaspar in the wake of the data-manipulation issue. Dr. Kaspar has denied wrongdoing in relation to the data manipulation, but didn't respond to requests for comment for this article.

The manipulation "is the antithesis of the culture we built," said a former AveXis executive, who said the vast majority of AveXis employees "were exceptional and did things with great integrity."

Although the FDA has allowed the drug to stay on the market, saying the data manipulation doesn't affect its efficacy or safety, the episode has nonetheless sowed worry among parents of babies with SMA. Cure SMA, a charity that raises money for research into SMA, quickly arranged a webinar with representatives from AveXis and the FDA to address concerns after the manipulation disclosures. One participant asked whether Zolgensma was safe, and if the FDA had been "duped" into approving it.

The FDA official on the call said the agency would have taken the treatment off the shelf if it had any doubts. Dozens of babies have been successfully treated with the drug. In some cases, babies who once would have struggled to sit up unassisted are now walking.

Eleven-month-old Isaac Olthoff was scheduled to receive Zolgensma when the data manipulation came to light. His mother, Michelle, said the announcement gave her pause, but she was soon reassured by the FDA's decision to keep the treatment on the market. Isaac received Zolgensma a week later.

--Joseph Walker contributed to this article.

Write to Denise Roland at Denise.Roland@wsj.com

(END) Dow Jones Newswires

September 14, 2019 02:47 ET (06:47 GMT)

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