When I first started writing about pharmaceuticals back in the early 1970s, I was a huge fan of generic drugs. I thought this was the best deal in health care. When pricey brand name meds lost their patents, a patient could request a less expensive generic formulation that would be “identical.” In those days, people paid for medicines out of pocket. Moreover, generic drug companies manufactured their products in the USA. But all that has changed. What’s worse, we have just stumbled onto another huge generic drug scandal that takes our breath away. And the FDA is right in the middle of this mess.
How Does the FDA Approve Generic Drugs?
Ask most doctors, nurses, pharmacists or hospital administrators how generic drugs make it to market and you are likely to get a blank stare. Push a little harder and about the best you will get is something like this:
“the Food and Drug Administration approves them and the FDA must know what it’s doing.”
It’s way more complicated than that! As far as the idea that “the FDA knows what it’s doing,” I am not so sure. The latest drug scandal involves generic Viagra, generic Cialis and potentially hundreds of other medications. Anna Edney for Blomberg (July 9, 2024), has revealed another generic drug mess.
First, the brand name drug companies do not have to reveal anything about their process for making the original formulation. The information is “proprietary.” And the FDA does not share such information with generic manufacturers.
Reverse Engineering:
The Cambridge Dictionary defines “reverse engineering” this way:
“the act of copying the product of another company by looking carefully at how it is made”
The Britannica Dictionary defines “reverse engineer” as:
“to study the parts of (something) to see how it was made and how it works so that you can make something that is like it”
During World War II both the Americans and Brits discovered that the Germans had created a very efficient gasoline can that did not leak. The allies reverse engineered the design and created “Jerry cans.”
These days there is all kinds of reverse-engineered software. This is also the process whereby generic drug companies attempt to mimic a brand name medicine and sell it for a lot less.
Reverse-Engineering Generic Drugs:
The problem is that recreating a brand name medicine from scratch is tricky business. Not only do you have to recreate the active pharmaceutical ingredient (API) but you have to add excipients (binders, fillers, colors, etc). Then the generic drug company has to put it all together so that the generic drug mimics the brand in the way it releases the API into the blood stream.
In the extraordinary book, Bottle of Lies, Katherine Eban details the process of reverse engineering and describes huge generic drug scandals. The Indian drug company Ranbaxy was trying to duplicate the prescription acne drug called Accutane. You can read the details of this generic drug scandal at this link. It’s worth a minute of your time!
The FDA Brags About Generic Drug Savings:
Generic drugs are big business. At least 90 percent of the medications that are dispensed in pharmacies are now generic.
According to the FDA, these low-cost knockoffs of brand name medicines “saved the U.S. health care system $2.2 trillion from 2009 to 2019.” That is a lot of money by any standard.
How good are these copycat pharmaceuticals? That is a question we have been asking for decades. To this day, we do not have a good answer.
The Food and Drug Administration maintains that:
“FDA-approved generic medicines work in the same way and provide the same clinical benefit and risks as their brand-name counterparts.”
The agency asserts that:
“The FDA Generic Drugs Program conducts a rigorous pre-approval review to make sure generic medicines meet these requirements.”
Is the FDA’s Trust in Testing Companies Warranted?
The problem is that the generic drug supply chain has a large number of links. Some of those links are surprisingly weak.
An early step in the FDA’s approval process requires that a generic drug company test its new formulation against the brand name it is trying to emulate. Most pharmaceutical manufacturers hire third party organizations to carry out these tests on human volunteers.
The companies that manage such clinical trials are usually called CROs (contract research organizations). What that means is that the CRO arranges for several dozen human subjects to come into a clinical laboratory facility. Half will get the brand name and half will get the generic knock off.
In theory, neither the subjects (who get paid) nor the investigators who conduct the study know who gets what. Typically, blood samples are taken hourly (or sometimes more frequently) over the course of a day. In theory, the generic medicine is supposed to parallel the brand name so closely that there is no clinical difference.
The generic drug company then submits the data to the FDA. If the bioequivalence drug curves are good enough, the FDA usually approves the lower-cost formulation.
Sadly, though, the agency does not make the data public so generic drug buyers or health care professionals can review it for themselves. The data are considered proprietary and therefore confidential.
The FDA has to rely upon the integrity of the CRO and the generic drug manufacturer to submit accurate data. That is not always the case.
When the Bioequivalence Data Are NOT Trustworthy:
The FDA has long reassured physicians, pharmacists and patients that generic drugs are every bit as good as their brand name counterparts. But no one is actually allowed to see the data. Are the results the FDA relies on reliable?
A Generic Drug Scandal Is Revealed:
The data generated by these contractors are absolutely critical for regulatory approval. Sometimes, though, the generic drug doesn’t perform as predicted.
Over a decade ago, the FDA missed problems at a Houston CRO called Cetero. But a whistle blower at the lab alleged that the company had manipulated data. The FDA eventually discovered that a lot of the drug data that had been submitted were fraudulent. You can read about “The Big Ooops” scandal at this link.
Later, the European Medicines Agency (EMA) recommended that more than a hundred generic drugs be pulled off the market.
According to the EMA:
“EMA’s human medicines committee (CHMP) has recommended the suspension of the marketing authorisations of several generic medicines tested by Synchron Research Services, a contract research organization (CRO) located in Ahmedabad, India.
“The recommendation comes after irregularities were found in how the CRO carried out bioequivalence studies, which raised serious concerns about the company’s quality management system and the reliability of data from that site. Bioequivalence studies are conducted to show that a generic medicine releases the same amount of active substance in the body as the reference medicine.
“The CHMP looked at all medicines tested by Synchron Research Services on behalf of EU companies and found that for the majority (around 100 medicines) no adequate bioequivalence data were available from other sources. The Committee recommended that these medicines be suspended.”
Perhaps you noted that the bioequivalence data generated by Synchron Research Services in Ahmedabad, India, was under suspicion. The most fundamental step in approving a copycat drug, the blood testing comparison between the brand and the generic, was questionable for around 100 medications.
The FDA and the Generic Drug Scandal!
European regulators are not the only ones who have found data that may be unreliable. In the fall of 2021, the FDA cited “a substantial data integrity problem” at two CROs (Pink Sheet, Oct. 11, 2021). One was Synchron, while the other was Panexcell Clinical Lab, located in Navi Mumbai, India.
According to Pink Sheet reporter Derrick Gingery,
“…the FDA determined after an extensive investigation that all study data from both firms should be rejected.”
The Pink Sheet is a pharmaceutical industry insider publication.
It states:
“A list of the concerned medicines has been published by the EMA, including products from leading generics players such as Accord, Jubilant, Lupin, Sandoz, Stada, Strides, Teva, Viatris and Zentiva.”
Fast Forward to June, 2024 and Synapse Labs:
On June 18, 2024 the FDA notified drug companies:
“…that clinical and bioanalytical studies conducted by Synapse Labs Pvt. Ltd. (Synapse)—a contract research organization (CRO) based in Pune, India—are not acceptable because of data integrity concerns. Studies conducted by Synapse must be repeated.
“During analyses of study data generated at Synapse and submitted in several applications, FDA identified significant unexplained anomalies in the data that indicate the data were falsified.”
The Bloomberg Big Reveal!
On July 9, 2024 Anna Edney of Bloomberg wrote about the faked data:
“Generic versions of erectile dysfunction drugs Viagra and Cialis, among other medications, were allowed on the US market using potentially problematic data that call into question their safety and efficacy, a Bloomberg analysis found.”
Ms. Edney went on to note that the data from Synapse Labs:
“…may have been used in hundreds of drugs, which remain available for sale on pharmacy shelves and in Americans’ medicine cabinets.”
“The FDA isn’t telling patients, doctors or pharmacists which drugs among thousands might be impacted because the agency said whether a drugmaker used a particular research company for hire is ‘confidential information,’ according to the FDA alert.”
How Did the FDA React to Such Generic Drug Scandals?
One might imagine that the FDA would follow the example of European regulators and act to get the relevant drugs off the market. The EMA also provided a list of all the affected drugs.
Back in September 2021 the FDA announced:
“FDA is changing the therapeutic equivalence rating to ‘BX’ for any approved ANDA [abbreviated new drug application] that relied on data from Synchron or Panexcell. A ‘BX’ rating indicates data reviewed by the agency are insufficient to determine therapeutic equivalence (substitutability) of the generic product to its brand name product. A drug with a ‘BX’ rating is still approved and can be prescribed but is not recommended as automatically substitutable at the pharmacy (or by a pharmacist) for the brand-name drug.”
What The Heck? BX or BS?
This issue may seem too technical to be of much interest to ordinary people. What it means in practice, though, is that the FDA is not banning any of the questionable drugs from the American marketplace. Instead, busy pharmacists have to figure out which generic drugs are not considered reliable.
It would be as if the FAA (Federal Aviation Administration) learned that the quality testing data for brakes on a jumbo jet made by company XYZ were unreliable and potentially fraudulent. Instead of banning those brakes and grounding the planes, though, the FAA left the decision to use the brakes entirely up to the company. That would be a huge scandal if it got out.
The American public would not want to fly on an airplane that did not have reliable safety data for its brakes. But the public would not be allowed to learn which airplanes were continuing to use bad brakes.
The FDA seems to be saying, Don’t Worry, Be Happy! So what if the Europeans are recalling/banning generic drugs that were approved based on fraudulent data? Here in the United States those drugs will stay on the market. We are leaving it up to pharmacists to decide whether to buy them and dispense them. We will just call those drugs “BX.” Some might call this idea BS.
In the most recent scandal regarding falsified CRO data from India, the FDA is not releasing information on the drugs in question. We suspect that the agency will cite confidentiality, even though European regulators have released a list of potentially problematic medications.
The Generic Drug Scandal Goes Way Back!
This is not the first time the FDA has learned that the critical bioequivalence testing process may have failed. Hundreds of generic drug products have likely been approved based on questionable data. Companies that have been under scrutiny in addition to Synapse labs, Synchron and Panexcell include GVK Biosciences, Semler and Micro Therapeutic Research Labs.
It has even happened in the U.S. As mentioned above, we document the crazy case of Cetero Research in Houston, Texas at this link. We encourage you to read our article, but here is a quick summary of this generic drug scandal:
There were three takeaways:
1) The FDA did not discover the fraud on its own
2) The FDA never told the American public which drugs were affected
3) The FDA never recalled or banned the drugs in question
We suspect that many, if not all, remain on the market to this day!
What to Make of These Generic Drug Scandals
What does all this mean for you? Can you trust your generic medicine?
The Europeans provide a complete list of products and manufacturers that are under suspicion. Because the FDA is not as transparent about such drugs, neither physicians nor patients have an easy way to evaluate the quality of their generic medicine.
Ask your doctor and your pharmacist if they have ever heard of a “BX” rating! We will bet you that most will have no idea what you are talking about.
Here, again, is the FDA double-talk that makes no sense to us:
“A “BX” rating indicates data reviewed by the agency are insufficient to determine therapeutic equivalence (substitutability) of the generic product to its brand name product. A drug with a “BX” rating is still approved and can be prescribed but is not recommended as automatically substitutable at the pharmacy (or by a pharmacist) for the brand-name drug.”
We think this seems a lot like Alice in Wonderland. What do you think? Please share your thoughts in the comment section below.
The CRO scandals are only the first link in the generic drug chain. Manufacturing problems and shipping concerns could also have an impact on the quality of many generic medicines. Until the FDA tests such products before they are sold to consumers, we have no way of knowing whether they live up to expectations.
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