Performance gap widening in some generic drugs, researchers say

To keep his anxiety under control, Peter, a 35-year-old government employee, relied for nine years on a blue-and-white pill he popped every night before bed: Cymbalta, made by Indianapolis-based Eli Lilly and Co. When a generic version came on the market, offering the chance to save money, he switched.

It didn’t work out. The old symptoms of anxiety resurfaced, along with some entirely new ones: “Irritability, and also it kind of felt like a blanket over your brain the whole time.” It didn’t occur to Peter to blame the medicine—he assumed it was the same as what he’d been taking all along. But his doctor, who’d seen similar reactions before, thought otherwise, and prescribed a return to Cymbalta.

“I feel remarkably better,” said Peter, three days after switching back. He asked not to be identified by his surname to keep his condition confidential. “It’s clear that the issue was with the generic,” he said.

From President Donald Trump down, Americans are acutely aware that they pay a lot for medicine. Trump says drugmakers have been “getting away with murder,” and promises action soon; whatever solution he comes up with, it’s likely to involve a bigger role for generics. They’ve already saved U.S. patients about $230 billion over three decades. For most people they work fine, as if they were identical to the brand-name equivalents. Which, in many cases, they aren’t.

“The average American has a series of assumptions about generic and brand-name drugs that don’t hold up to historical scrutiny,” said Jeremy Greene, a professor of the history of medicine at the Johns Hopkins University in Baltimore.

Drip-feed

There are two reasons why the performance gap may be widening.

First, medicines—especially those that treat conditions such as anxiety or depression—are becoming more complex. It’s not just the mix of active ingredients that generic drugmakers have to replicate. It’s also the release mechanism, which controls how those ingredients are absorbed—for example, by delaying or drip-feeding their entry into the system so that a patient only needs to take one pill a day.

That technology, often known as extended release, is covered by separate patents, so it’s often not available to the generic producers. They have to create their own versions, which may not work the same way. The FDA is studying ways to better assess the risks that arise from those differences. It says that about one-third of the 200 most-prescribed drugs in the U.S. rely on such mechanisms.

Second, a growing share of the pharmaceuticals on sale in America are produced in low-cost countries like India and China, and often tested there too. The U.S. Food and Drug Administration has found cases where data may have been manipulated during the quality-testing. But, as it struggles to regulate the vast local industries from understaffed bureaus, the FDA’s efforts amount to a drop in the ocean.

The story of Cymbalta and its rivals involves both sets of problems—matching release mechanisms, and emerging-market production. And it features two generic-makers that have run into similar trouble in the past.

In 2014, the first year generic versions of Cymbalta were on the market, the FDA received 262 complaints from patients who switched, or from their doctors, according to a review of so-called adverse event reports obtained by Bloomberg through the Freedom of Information Act. That’s more than five times the number of complaints about the effectiveness of Lilly’s brand-name drug recorded in the U.S. the previous year.

“What we can definitely say is there is increased reporting in a sustained fashion that stands out,” said Libbe Englander, chief executive officer of Pharm3r, a company that analyzes medical data, after reviewing the records for Cymbalta and the generics.

The generic drugmaker associated with the largest number of complaints was India-based Lupin Ltd., which accounted for 61 of them. Another 47 of the patients had used a version made by Israel’s Teva Pharmaceutical Industries Ltd. Both companies said there were no problems with their versions, and the FDA agrees.

“Teva stands behind the safety and efficacy of all our medicines, when used as prescribed,” spokeswoman Elizabeth DeLuca said in an email. Lupin said it’s complied with all FDA-mandated testing and its generic drug “meets all requirements to ensure that our product is effective and safe.”

The FDA believes all generic versions of Cymbalta are safe, effective and equivalent to Lilly’s brand-name drug, said Sandy Walsh, an agency spokeswoman. New generics, especially those that treat depression, “tend to elicit a large number of patient complaints typically within the first year after approval,” Walsh said in an emailed response to questions.

The same two companies topped the list of complaints made about generic Cymbalta in 2015 and 2016, too, accounting for 115 out of a total of 281 cases reported by patients who had either switched from the branded drug, or started on the generic and found it ineffective. Some reports don’t mention any company by name, because patients aren’t always aware of who makes the medicines they take. Peter, for example, didn’t know which company’s generic Cymbalta he initially switched to, although from October 2015 he was using Lupin’s version.

In Lupin’s case, the European Union’s pharmaceuticals regulator recommended in 2016 that EU member countries should ban the company’s generic Cymbalta.

‘Called Into question’

What troubled the European agency was precisely the question of how the medicine’s ingredients are absorbed. The process of establishing whether that works the same way for generic drugs as it does for the brand-name originals is called bioequivalence testing. For its Europe-bound version of Cymbalta, Lupin used India-based Semler Research Centre to carry out those tests. The European Medicines Agency said that inspections had “called into question the quality management system in place at Semler, and thus the reliability of the data of all bioequivalence studies.”

Semler couldn’t immediately be reached for comment. In any case, Lupin said it used a different researcher to conduct tests for the generic Cymbalta sold in America. “The product has proven to be bioequivalent to the branded drug,” Lupin’s press office said.

Like its European counterpart, the FDA has raised concerns in the past about drugmakers and researchers in China as well as India. More than 80 percent of the ingredients in U.S. drugs are produced in those two countries. The FDA carries out its own inspections in both, sometimes in collaboration with European peers.

The agency is seeking to step up that kind of work, but it’s running into capacity constraints. There are multiple vacancies in its New Delhi and Beijing offices. As of July 2016, 11 investigators were on staff in China out of an authorized 18, according to a Government Accountability Office report from January. In India, the situation was even worse—three out of 13. Even for a fully-staffed bureau, monitoring hundreds of local producers would be a daunting task.

It’s not clear where Teva, which has plants in India and China among several other countries, makes its generic Cymbalta: That’s proprietary information the company doesn’t have to disclose.

But Teva was involved in a controversy a decade ago with parallels to the Cymbalta story. It was one of two companies authorized to sell versions of GlaxoSmithKline’s Wellbutrin, an extended-release anti-depression drug. In the first six months that the generics were on the market, in 2007, the FDA received 85 complaints that switching had caused problems.

The agency decided to conduct its own study. It found that Teva’s generic 300-milligram version failed to release the active ingredient into the blood at the same rate as the brand-name drug. Teva pulled its medicine off the market in 2012.

It’s not necessary to have an identical release technology. Generics can achieve the same effects as the original drug provided they have “the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence,” Teva spokeswoman Denise Bradley said by email.

But Joe Graedon, who heads an online pharmacy forum called The People’s Pharmacy, warned the FDA about problems with generic Wellbutrin at the time. And he says he’s seeing history repeat itself with Cymbalta.

“We’ve got very similar reports of what people went through when they switched,” Graedon said. “Their depression came back. They were crying more.” And they experienced symptoms of overdosing on the active ingredient, because release mechanisms weren’t working properly. “Insomnia, headache, gastrointestinal distress. They were getting too much drug too fast. And not enough throughout the day.”