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With the U.S. increasingly dependent on foreign manufacturers for prescription and generic drugs, the Food and Drug Administration’s problem-plagued efforts to inspect overseas plants is under growing scrutiny.
A recent report by the Government Accountability Office has raised serious concerns about the FDA’s foreign inspection program and whether it’s allowing overseas drug makers to conceal unsafe practices. The number of inspections performed by the agency has been falling since 2016, due to dozens of unfilled positions.
The inspections that the FDA does perform are riddled with problems, according to the report. For example: because the FDA doesn’t have enough translators, inspectors are often forced to rely on the drug manufacturer to provide one – which, according to the report, “can raise questions about the accuracy of information FDA investigators collect.” And unlike domestic inspections, which are all unannounced, the vast majority of overseas firms have months of advance warning of an FDA visit, giving them plenty of time to prepare.
“That’s just an unacceptable practice, to announce most of these inspections,” said Michael Carome, director of the health research group at Public Citizen, the consumer advocacy organization. “It gives companies a chance to destroy documents, manipulate documents and clean up a facility.”
The United States is more reliant than ever on other countries for its supply of pharmaceutical drugs. According to the FDA, roughly 40 percent of finished drugs and 80 percent of active drug ingredients are made overseas.
The FDA is tasked with regularly inspecting drug manufacturing facilities in the U.S. and abroad to ensure they’re following best practices.
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“We’ve created a scenario where we don’t have the capacity to make a lot of those products in the U.S.,” said C. Michael White, head of the Department of Pharmacy Practice at the University of Connecticut. “We’ve concentrated them in areas where we have very little control, and very little knowledge of what they’re doing.”
Allegations of attempted coverups abound. In October of 2018, an FDA investigator at Strides Pharma Science Limited in India discovered bags of documents awaiting shredding and a binder full of records dated seven days before the inspection, discarded in a 55-gallon drum in the plant’s scrap yard. According to the warning letter, made available on the FDA’s website, the company told the FDA that the binder had “inadvertently come [sic] to scrap yard.”
In testimony before the House Subcommittee on Oversight and Investigations, FDA official Janet Woodcock admitted that more unannounced visits would be “desirable,” although she added they were “inefficient” because of the enormous size of most drug plants and number of staff needed to assemble.
“It is just a hypothesis that unannounced visits are so much better,” said Woodcock, director of the FDA’s Center for Drug Evaluation and Research. “A lot of problems have been found by announced inspections.”
Indeed they have. The August 2018 investigation of B. Jain Pharmaceuticals in India found “numerous flying insects,” including a live moth, in a raw material storage room, and the ceiling of the quarantine room “stained with what appeared to be mold,” according to the resulting warning letter. An investigator visited Cadila Healthcare in India in May of 2019 and discovered “significant equipment flaws and cleaning deficiencies” which “resulted in cross-contamination between your drug products.” The firm claimed the cross-contamination did not pose a risk to patients, a response the FDA said was ”not scientifically sound.”
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An investigator at Centurion Laboratories in India found, in October 2018, “visible product build-up” in a room that had been marked as “cleaned,” as well as a damaged air filter full of holes. Centurion chalked these deficiencies up to “a shortage in manpower related to a nine-day dancing festival and government holiday.”
Such negligence can lead to the drugs or active ingredients being adulterated. Taking them can have a range of effects, from the innocuous to the fatal. In 2008, a tainted supply of the blood thinning drug Heparin led to 81 deaths and 785 severe injuries worldwide. Researchers traced the contamination back to a Chinese factory which had never been inspected.
The crisis, said White, “would have been mitigated if [the FDA] had done more inspections. It would have been mitigated, also, if we didn’t also have all our eggs in one basket, so that we weren’t so reliant on China to supply the active ingredient for that one product.”
Up until then, the FDA inspected domestic facilities every two years, but only performed a few hundred overseas inspections per year. After the 2008 Heparin crisis, the FDA shifted resources away from domestic inspections and toward foreign inspections, with the number of foreign inspections rising to more than 1,000 in 2016. A GAO report published that year lauded the improvements, but warned of a startlingly high vacancy rate among the agency’s inspector corps.
According to the recent report, the FDA still has 66 vacant inspector positions based in the U.S and numerous other vacancies in the FDA’s foreign offices. In her testimony, Woodcock said the agency was in the process of hiring 20 more investigators, but warned that it can take years for candidates to pass background checks and go through training.
“The fact that we have these vacancies and we see a falling number of inspections tells me the agency isn’t giving this matter a high enough priority,” said Carome. “The FDA certainly doesn’t have a problem meeting goals for approval of new drugs and getting those to the market as soon as possible.”There is perhaps an inherent tension between the FDA’s two goals of ensuring that pharmaceutical drugs are safe, but also making sure enough drugs are manufactured to avoid shortages or excessively high prices. Generic drugs, which are mostly made overseas, help bring down the cost of prescription drugs. But unlike clothes, drugs don’t come with labels saying where they were made. And in any case, the average customer may not have much choice, since individual pharmacies decide which generics to stock.
“Patients in the U.S. don’t have a choice today,” said Dinesh Thakur, a former Ranbaxy executive who became a whistleblower, helping to expose massive fraud within the Indian pharmaceutical company. “You don’t have the ability to demand medicine from a certain country.”
Since generic drug manufacturers are only competing with each other on price, some resort to cutting corners. The FDA, meanwhile, is under pressure from lawmakers to increase the supply of generic drugs to lower the cost of health care.
“It raises the question of whether the FDA really wants to know what’s going on in those plants,” said Katherine Eban, author of the book, “Bottle of Lies: The Inside Story of the Generic Drug Boom.” “Because that can lead to difficult regulatory action.”
The FDA has a history of softening its own negative inspection findings. In 1998, the GAO found that in the previous year, the FDA had downgraded roughly two-thirds of the recommendations for enforcement actions made by inspectors. According to Eban’s reporting, the FDA downgraded recommended sanctions against Indian plants 109 times between 2013 and 2018. During that same time period, the agency downgraded sanctions against U.S. plants just once. The GAO plans to examine the downgrades in a future report.
Said Eban: “The FDA is knowingly allowing unsafe, substandard drugs from noncompliant plants into the U.S., over the recommendations of its own investigators.”
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I was recently very surprised finding this story about Alkem and heart medicine.
https://www.bloomberg.com/news/articles/2019-05-16/swarms-of-bugs-missing-data-plague-firms-now-making-heart-drug
But the situation at the U.S. pharmacies is just as worrisome:
https://www.nytimes.com/2020/01/31/health/pharmacists-medication-errors.html
This report could be buttressed with an authoritative list of generic drugs pulled from the market. Valsartan, a widely used treatment for hypertension, was recalled for containing cancer-causing chemicals.
[…] By GGCRBHS&M A lack of of FDA inspections abroad may result in unsafe drugs for patients. 60% of the drugs sold on the American market are coming from foreign countries and 80% of their ingredients are also coming from abroad manufacturing facilities. As a result the FDA send inspectors abroad to make sure drugs are manufactured in a safe environment. In 2018, 57% of the FDA drug inspections occurred in foreign countries mostly China and India. Since 2016 the number of inspections has been declining because the FDA hasn’t been able to find qualified investigators or hasn’t dedicated enough time to look for them. Additionally, investigations in India and China have been found particularly challenging with the FDA being unable to conduct unannounced inspections. Announced inspections give time to manufacturers to clean the facilities or “rearrange” their papers to pass the inspection. In some cases even though the inspection was announced, inspectors found significant problems mostly related to equipment flaws and cleaning problems. Such problems can lead to cross-contamination between drug products or to alteration of the drug products. In 2008, 81 people died and 785 suffered severe injuries after using a tainted batch of Heparin, a blood thinner, coming from a Chinese factory that had never been inspected. Additionally, according to a recent article in Fair Warning, the FDA has a history of softening its own negative inspection findings and downgrading sanctions against pharmaceuticals. This raises the concern that the FDA is after all not that concerned as to what is going on in pharmaceutical manufacturing facilities abroad. Read the entire article in Fair Warning […]
I had used some generic brand that I don’t remember many years ago of Metatropal for heart palpitations with no side effects,and last year my nurse practitioner prescribed it to help lower my recently diagnosed high blood pressure,and I felt sick as soon as I took it,and I took it for days hoping my body would get used to it and adjust to it,but it didn’t!
Then I asked for a different generic and I felt 100 times better, but it wasn’t lowering my blood pressure that much so the nurse practitioner prescribed 50mg of Losartan with 12.5 HCTZ, but this wasn’t lowering my blood pressure enough,and I tried 100 mg but it was too strong and upset my stomach and made feel sick,so I asked the nurse practitioner to prescribe 25 mg of Losartan without the diuretic, in addition and that only lowered it a little more.
And my pharmacy first had given me the generic brand Alembic for the 50 mg of Losartan,which was a softer different shaped pill,and I can’t swallow pills,and this pill doesn’t have a line that I can cut with my pill cutter, so I have to wet it with a drink and bite it into two pieces,and then my pharmacy switched to another brand, I don’t what it is because they just have the abbreviation of the name,but it’s a much harder pill so it’s harder to bite it, I have to wet it longer in my mouth,and the pharmacy says they can’t get the other brand anymore.
I had hardly slept at all in several months after being diagnosed with high blood pressure and the medications not lowering it enough, I was terrified that I was going to have a stroke or heart attack in my sleep. Finally the doctor who works in the same home MD practice came and met with me only once in February 2019 and he prescribed 25 mg of a beta blocker,Atenolol in addition to both Losartan medicines, and at first after taking it for a little while it reduced my blood pressure down to normal where it used to be not that long before when I had normal blood pressure without any medicine.
I had no bad side effects taking this,until my pharmacy switched to another generic which made me sick,so I asked them to please get the first brand and they did and they even told me this is the brand they usually get.
My blood pressure has gone up a little though since I had first started taking it.Just very recently after I had been taking the 25 mg of Losartan of the brand Aurobindo for 3 months which was a light green pill,my pharmacy had switched generics to a white pill that made me feel sick as soon as I took it,but I took it several days alternating with the other brand that I had about 2 weeks worth left of,hoping my body would adjust to it,but this never happens.
It turns out that this is the same brand of Losartan,the Indian company Camber including 25 mg,with the same exact NDC number,and including a 90 day supply,that the FDA recalled just months before in February 2019 for having a cancer causing ingredient NMBA!
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/camber-pharmaceuticals-inc-issues-voluntary-nationwide-recall-losartan-potassium-tablets-usp-25-mg
Camber Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25 mg, 50 mg and 100 mg Due to the Detection of Trace Amounts of N-Nitroso N-Methyl 4-amino butyric acid (NMBA) Impurity found in the Active Pharmaceutical Ingredient (API) | FDA
This recall was prompted due to the detection of trace amounts of N-Nitroso N-Methyl 4-amino butyric acid (NMBA) a possible process impurity or contaminant in an active pharmaceutical ingredient …
http://www.fda.gov
So I called the pharmacy and told them about this and asked if they could please get the other brand back,and they said to call back in a few days after the pharmacist I spoke with said she would ask the woman who is in charge of ordering the medicines,and when I called days later she told me that they can’t get this brand anymore and suggested I call other pharmacies and see if they have it and they would transfer my prescription over to them.
So I called CVS who I used to go to for years and who are only about a walking block away,and they do carry this generic,so I had to call my nurse practitioner and get a new prescription since it was already recently filled for a 90 day supply.But my insurance company said it was too soon to refill it,and they did this for me before when I had a situation like this,so I called my nurse practitioner and asked her to please call my insurance company and explain the situation and get an override for the new prescription,but she actually refused and said it’s my responsibility to call,and that’s not really true,most of the time the insurance company needs to have the doctor call about this.
And this is even after the nurse practitioner had just been at my house days before checking my blood pressure,and she told me the same thing she told me before when I felt sick on the other generics,that she believes me because one of her patients was taking the same pain medication for years that was helping her with her pain,and then the pharmacy switched to a different generic and it did nothing for her pain.
And just recently before she said I should tell the pharmacists that they should make a note of what generic brands make me sick,and I said I already did this,and she said big pharmacies don’t really care about this,private pharmacies care more.I even had told her that CVS and my insurance company said they can’t fill the new prescription with the other generic until November 5,and this was October 1, so she actually expected me to take a generic medicine for a month and 5 days that was making me feel sick,and it’s a necessary medicine that I have to take to lower my blood pressure!
So I called CVS back and I asked them how much it would cost to pay for this prescription,and the woman I spoke to said a 90 day supply would cost a 100$ which I can’t afford,so she said do you want me to check a 30 day supply,so I said yes,she told me it would be 44$ so I asked isn’t there any discount? And she checked something with a card,and found me in their system from years ago,and said yes,there is and a month supply is 11.88 so I had to buy it out of my own pocket which is really wrong.
My nurse practitioner had called my insurance company many months before and said she was on the phone with them almost 3 hours to get the brand name of Benicar for blood pressure because my father has been taking it for 20 years and it really lowered his blood pressure,but unfortunately it caused my IBS to act up bad and I had to go back on the Losartan,this was before the doctor had prescribed the Atenolol in addition to the Losartan medicines.
I recently asked my pharmacy to get a different generic of Xanax because it was making me feel not well,and they did get a different brand but I only felt a little bit better, I never had a problem with other generics of it from different pharmacies in the past.Also I have IBS for 26 years now off and on with bad pain,which goes away for 4 or 5 months,but unfortunately comes back,and that’s the only symptom I ever got from it,well a GI doctor prescribed the only medicine that finally took my pain away, it was the Mylan brand of Bentyl which I took for years,and then when pharmacies switched generics I tried 3 others including a liquid and none of them took the pain away like the Mylan brand did,and I used to open up the little capsule and mix it in sugar free flavored water because I can’t swallow pills,( although recently I have been able to swallow the little capsule) and only the Mylan brand dissolved in the water.
But the Mylan brand has been on back order for the Bentyl for so long,first they told me in January of this year they were going to have it by February,then I call in February and they now claimed they were going to get it in September,so I forgot about them and luckily I tried a new brand that also really helps with the pain,and I really hope that my pharmacy continues to get it in,they said they usually get that brand.
Some pharmacists I have spoken with act as if they don’t know or understand that it’s a reality and fact that different inactive ingredients do have different side effects on many people,and or are not effective,but I had spoken to several pharmacists in the past who did say they know that certain fillers and inactive ingredients in different generics can do this.
It’s really wrong and terrible that pharmacies can and do, do this to patients! I’m no longer seeing this nurse practitioner and I need a primary care doctor now.
How Differences Among Generics Might Effect Your Patient’s Response by psychiatry and pharmacy professor Vicki L Ellingrod University Of Michigan
https://mdedge-files-live.s3.us-east-2.amazonaws.com/files/s3fs-public/Document/September-2017/0905CP_SavvyPsych.pdf
https://www.drugs.com/answers/different-manufacturer-generic-drugs-different-3293748.html
Can different manufacturers of same generic drugs have different side effects?
Absolutely!! It’s difficult to find information confirming this, on line, but I can speak from personal experience in saying that with some medications I have noticed differences in efficacy and side effects when I have had to change to a different pharmacy that uses a different manufacturer for their generics.
http://www.drugs.com
https://www.quora.com/How-can-the-same-prescription-drug-made-by-different-manufacturers-cause-different-side-effects
How can the same prescription drug made by different manufacturers cause different side effects? – Quora
While the active ingredient remains the same, different manufacturers use different inactive ingredients as the binders and fillers. Different manufacturers may also use different colorings and coatings, all which could cause different side effect…
https://www.google.com/search?q=Can+Different+Manufacturers+of+The+same+Generic+Drugs+have+different+side+effects%3F&rlz=1C1SQJL_enUS849US849&sxsrf=ACYBGNRd1q764yVSfL9od2_EWx5Z3VMNeA:1576094925318&ei=zUzxXZT3Esi3ggfn67TYDg&start=0&sa=N&ved=2ahUKEwjUkZ-Rs67mAhXIm-AKHec1Des4ChDy0wN6BAgLEC0&biw=1139&bih=577