Is FDA really the “gold standard” in drug safety?
By: Gabriel Levitt
Tags: FDA, American Dream, Drug Prices, Healthcare, Drug Safety

Opponents of Americans buying less expensive drugs from overseas pharmacies (i.e. personal importation) often rely on the common belief that the U.S. Food and Drug Administration exemplifies the “gold standard” in drug safety. This “gold standard” importation talking point from the Pharmaceutical and Researchers of America (PhRMA) fuels Americans’ fear of ordering medication internationally despite proof that importation can be very safe and provide financial relief and better adherence to prescriptions:

“The United States is the gold standard when it comes to regulating the safety of our medicine supply. Importing medicines from countries that do not have our same strong standards could taint our medicine supply.”

The first sentence is something you are supposed to take at face value. The second sentence is deceptively broad: as in, yes, importing medicines from countries that do not have our “same” standards could taint our medicine supply. Not necessarily, but it could.

If the U.S. is not the gold standard in drug safety, it would fatally weaken anti-importation arguments.

Testimony this week by the Government Accountability Office before the House Energy and Commerce Subcommittee on Oversight and Investigations about the FDA’s potential failures to protect the public health shows that things may not be so golden. The FDA’s continuing problems with inspections of drug manufacturing plants, as well as the relative comparative strength of other drug regulators, ought to inspire serious reflection, even introspection, among drug safety policy professionals about whether or not, and how, we have the gold standard.

The GAO’s preliminary analysis on inspections brings back into light what Katherine Eban so passionately — and dramatically — exposed in her book Bottle of Lies: The Inside Story of the Generic Drug Boom.” Eban walked us through the corruption and negligence among pharmaceutical manufacturers but also at the FDA, which has led to far more instances of substandard drugs than most people know.

The GAO’s report sharpens Eban’s point on why we will continue to see quality problems without improvements. According to the GAO, there were fewer domestic and foreign inspections from 2016–2018, 10% and 13% fewer respectively, after an increase between 2012–2016 that followed passage of the Food and Drug Administration Safety and Innovation Act of 2012.

Job vacancies seem to be endemic for foreign drug establishment FDA inspectors. Out of 168 available positions for U.S.-based inspectors who go overseas, 66 remained unfilled. For foreign-based inspectors, the vacancy rate in China and India was 30% and 33%, respectively.

A majority of inspections resulted in findings of non-compliance. Between 2012–2018, inspectors found “deficiencies” in 64% and 59% of foreign and domestic establishments, respectively. Perhaps most troubling is that when inspectors’ findings included the most severe designation, called Official Action Indicated, the FDA’s Center for Research and Development (CEDR) downgraded that determination to Voluntary Action Indicated. The GAO plans to follow up on that to find out why.

The GAO also reported that foreign inspections are usually pre-announced by 12 weeks, whereas domestic inspections maintain the element of surprise. The FDA inspectors often must rely on translators hired by the drug companies, where the best option is having independent translators onsite. To make matters worse, the FDA did not know exactly how many inspections were pre-announced vs. those that were not. The FDA told the GAO that the agency “does not have a data field in its database to systematically track this information.” Add one.

There are certainly strong counterpoints against the above criticisms, including the ones I wrote about in defense of the FDA’s overall public health mission and work. I pointed out that the last two decades have actually seen improvements in the FDA’s drug plant inspection program. Those improvements were also duly noted in the GAO’s report. The reality is that in 2008 the FDA’s inspection database was kind of a complete mess (there’s no need to put that eloquently). GAO stated:

“In our 2008 report we found that, because of inaccurate information in FDA’s databases, the agency did not know how many foreign drug establishments were subject to inspection.”

In 2018, an estimated 8% of foreign establishments subject to inspection were actually inspected. Today, the FDA tells the GAO that 1,000 foreign establishments without an inspection record in 2017 have either all been inspected or were no longer subject to inspection.

What about other countries? The European Union (EU) has similar challenges to us when it comes to drug safety, including inspections of the plants that make pharmaceuticals for the European market. In fact, they have the exact same problems as we do in ensuring that the active pharmaceutical ingredients (APIs) used to make our drugs are of the highest quality and without contaminants. Why do I write “exact same”? Because sometimes we’re dealing with same factories making the same APIs, which turn out to have problems. In 2018, as reported in FiercePharma, on the same day the EU revoked its certificate of approval from a Chinese manufacturer Zhejiang Huahai due to impurities found in its Valsartan API, the FDA slapped an import alert on the same company banning its products.

The two agencies realize that they need to cooperate more for better results and acted on that realization. Clearly, the FDA acknowledges the relative strength of the EU on drug safety. That’s why increasingly the FDA is relying on inspections from EU member countries in lieu of an FDA inspection through the U.S.-EU Mutual Recognition Agreement, which the FDA titles “A New World for Pharmaceutical Inspections.” They both require the most advanced cGMP or current Good Manufacturing Practices. This quote from Pearl Pathways sums it up nicely:

“The Mutual Recognition Agreement allows EMA and FDA to optimize their inspection capacity and eliminate the need for inspections from multiple agencies. This will enable patients to trust the safety, identity, strength, purity, and quality of all medicines, no matter where the products are manufactured or which agency inspected the manufacturer.”

When it comes to the approval of new drugs, brand and generic, the systems of the U.S. and the EU are very similar. The two agencies almost always agree on which drugs should be approved, although there is some dialog of a potential growing divergence. For each drug regulatory authority, before a drug is approved, three phases of clinical trials of increasing complexity and scope in human subjects and proof that a drug will be manufactured correctly under Current Good Manufacturing Practices are required. Both the EU and the U.S. also track a drug’s safety even after approval, by detecting, recording and monitoring a drug’s side effects, which is called pharmacovigilance.

For an excellent overview of the EU’s regulatory system, see: Excellent overview of the European Union’s drug regulatory system

For a longer report about the U.S drug regulatory system, see: How FDA Approves Drugs and Regulates Their Safety and Effectiveness

When it comes to a system of track and trace of approved prescription drugs through their respective supply chains, which help prevent fake meds, the EU is ahead of the U.S. The EU already mandates full compliance with the Falsified Medicines Directive (FMD). FMD requires that every single prescription drug dispensed in the EU must be verified for authenticity via a mandatory 2D barcode on the packaging. The U.S. counterpart, the Drug Supply Chain Security Act (DSCSA) doesn’t come into full force until 2023. Also, the DSCSA doesn’t require verification of all dispensed drugs, but only requires the ability to do so if there’s a suspect product.

See: FMD (EU) and DSCSA (US) — how they differ

Is the EU now the gold standard for combating drug quality problems and fake meds?

According to product safety and quality experts at Mettler and Toledo: “Europe and the United States are considered the world leaders in the safest pharmaceutical markets for patients.” I agree with this 100%.

For the reasons stated above: an American who is able to safely import a drug from a licensed pharmacy in the European Union or the UK (!), assumes no additional health risks different from those present at a local Walgreens. And, as discovered in research from the House Ways and Means Committee and PharmacyChecker, the drug prices will often be about 72% less.

We can no longer afford to accept Pharma’s Alice in Wonderland arguments against drug importation. Let’s step back through the looking glass to see things as they really are: Drugs in the European Union are just as safe as they are here. Maybe Canada is too small a market but the European Union has over half a trillion people, much bigger than the U.S. That makes the prospect for importation very real.