‘Scary World’ of Generic Drug Manufacturing, Revealed
https://www.medscape.com/viewarticle/914067#vp_1
In 2008, investigative journalist Katherine Eban started digging into the generic drug industry after hearing stories of patients whose generic drugs were not working properly for them. They had been stable on a branded drug, but then relapsed once switched to a generic version or experienced troubling side effects when switched between generics. She detailed her findings in a series of articles in the magazines Self and Fortune, and her new book, Bottle of Lies .
Katherine Eban. Robert Falck
The majority of generic drugs are manufactured overseas, and “the [US Food and Drug Administration] FDA was essentially regulating on an honor system,” Eban told Medscape Medical News. The agency would announce its inspections of overseas manufacturing plants weeks or months in advance, giving companies an opportunity to prepare to put on a good face and mislead inspectors with fabricated data.
In the course of Eban’s reporting, she obtained 20,000 internal FDA documents that “revealed that the FDA’s investigators have grave doubts about the quality of the drugs being manufactured at these plants,” she said. But FDA officials minimized the investigators’ findings.
Eban spoke with Medscape Medical News about the implications of her findings for clinicians. The following is a lightly edited account of the conversation.
Medscape Medical News: What do you think doctors and other healthcare professionals need to know about the state of generic drugs?
Katherine Eban: In the book I feature several doctors from the Cleveland Clinic who struggled with this question of the quality of generics. A number of heart transplant patients suffered organ rejection after being switched to a generic tacrolimus. And also a number of patients who were followed by a cardiologist who became very intently focused on this question and felt he couldn’t stabilize them on certain generics.
He actually identified drugs that were particularly problematic, and after he identified them, lo and behold, the FDA went into the plants, found egregious conditions, and those drugs were recalled. So he was observing something that really is going on.
What I think physicians need to understand is, if their patient is not responding as anticipated from a medication, they need to consider the possibility that it is the medication that is the problem. So instead of just increasing a dose, or switching a patient to a different therapy altogether, I think they need to consider, is this the manufacturer of this generic? Is there a better generic that I can get the patient switched to? Or do I need to make a case to the patient’s insurance company that they should be on the brand? And it’s just a kind of category of thought that physicians need to have.
What role did physicians play in helping these issues come to light?
The doctors that I’ve talked to who have become aware of this, and have petitioned the FDA about this, I think [they] played a major role in having this come to light.
I think without their clinical vigilance, I’m not sure it ever would have come to light. But it’s no accident that it took me essentially 10 years of reporting to produce this book. It’s very complicated. And it requires a lot of connecting of the dots, from clinical symptoms, to the global drug supply, to regulatory failures, to what’s actually happening in these manufacturing plants. It’s a lot of data points to line up. And I think that’s one of the reasons why it hasn’t really come to light before this.
What discovery from your reporting for this book surprised you the most?
The level of data fabrication is really extraordinary. I’ll give you an example.
Because of some of the findings in the plants, the FDA ran a pilot program in India, from 2014 to mid-2015. They decided all the inspections were going to be unannounced or on very short notice, which obviously should be the standard. Once they started going into these plants completely unannounced, what they discovered was just staggering.
The plants operate data fabrication teams that come in in advance of FDA inspections. They alter data, they invent documents, they even invent standard operating procedures that don’t exist. One plant steamed them overnight to make the documents look old. They found out another plant was completely fabricating its testing to prove that the plant was sterile. There were no tests. The laboratory that was doing this was testing nothing, and all their data were perfect. So that’s an example of the kind of depth and extent of the fraud in these plants. It’s shocking.
Is there anything that doctors can do to help their patients avoid these poor-quality generic drugs?
Once doctors become aware of this issue, as their patients have symptoms, or as they have difficulty, I think [doctors] will find that there are certain manufacturers where they have repeated problems, and then when they switch to different manufacturers, everything is OK.
As difficult as it sounds, I think that doctors really have to get to know some of these manufacturers. I think the medical community and the patient community have taken it pretty much on faith from the FDA that all the drugs are interchangeable. That you can just switch from one brand to a generic or between generics and it’s all the same, except that’s really not the case. Once doctors become aware of that, I believe you’re going to find that drugs from certain companies are pretty reliable, and drugs from other companies are not, and that becomes a way to get to the bottom of this more quickly.
What is the role of listening to patients about their reactions after switching to a new generic drug?
Listening to patients is absolutely vital. In the first article I wrote about this, I interviewed this woman who was switched at the pharmacy from a brand name to a generic antidepressant, and had just a horrible set of reactions and side effects. [She] ended up going from doctor to doctor to try to treat all those side effects because she didn’t realize that it was her generic. She finally went online and began doing her own research and began to connect the dots and realize that the onset of her symptoms was at the point that she was switched to a new medication. She called her doctor’s office and the nurse at the doctor’s office said, “Yeah, we hear this from a lot of patients.” Had she had that information previously, she would not have been on this horrible medical odyssey.
Doctors can play a huge role in helping patients with this. Frankly, we need new legislation around this, but that’s not going to happen anytime soon, most likely. So until these problems can get addressed, doctors are really the front line in dealing with it.
What about the role of pharmacists?
My impression is that most pharmacists don’t really know about these issues, and that they also don’t really know where drugs are manufactured. It’s not their fault. What they know is what they have on the shelf at any given time, which is in these big bottles that they’re filling prescriptions from. I think a lot of states don’t even require pharmacies to maintain records of which manufacturer they dispense. The recalls often don’t even get down to the patient level because of that.
To the extent that they talk to consumers, I think [pharmacists] can play a key role in helping them. For example, there are manufacturers whose drugs I won’t take. And my pharmacist knows that I’m a bit of a pain when I go to fill a prescription, but there are just certain companies — because I know that they fabricated data, that their plants are not sterile, that they’ve gotten FDA warning letters — I won’t take a prescription filled with their medicines. And my pharmacist knows that. They let me switch to a different manufacturer. I often am requesting specific generic manufacturers that I trust more than others. But I think if the pharmacist doesn’t understand these issues, that’s going to seem like very strange behavior to them. So it’s something I think that they need to be educated about, too.
One thing that I know a lot of experts in this space really think is important is putting the country of origin, of manufacturing, on dispensing labels. Why shouldn’t consumers know where the active ingredient and the finished drug are made? Why isn’t that information passed along to patients? That is something that could be a sort of educational tool for everybody in this space.
In addition to your book, what are some other key resources to keep up to date on what’s happening with generic drugs at the FDA and which manufacturers have an issue?
On the FDA website there are links to warning letters and import alerts. There’s another site that I like a lot called FDAzilla, which has all of the documents related to FDA inspections on it. If your patient is reacting badly to a drug made by company X, you could go into FDAzilla and look up the inspection record of that company. But for busy physicians, it’s not so easy.
The category of findings related to falsification is called data integrity. The whole idea behind “good manufacturing practices” is that you can’t test the quality of a million pills in a batch. So consequently, good manufacturing requires a kind of minute-by-minute creation of data that accompanies each step of the manufacturing practice. And that data is considered the cornerstone of good manufacturing practices. Without that data, there’s no way to vouch for a drug’s quality. If a company has data-integrity issues, it’s a pretty scary world. It means that there is a real possibility that they’re committing fraud. Not a guarantee, because you can have data-integrity findings that are not necessarily fraud, but negligence, or just problems, but it’s kind of a red flag. And that’s something for doctors to be aware of.
Doctors who are inclined to be political about this should contact their lawmakers. Because it’s really a very difficult, almost intolerable situation that we’re in. I think there needs to be medical activism on this issue.
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