Generic = Branded Drug, What are the Facts?

Are generic drugs really as effective as brand-name drugs? This is what is introduced in the textbook, but many people have had different experiences in real life, and now even the US political and military do not fully agree with the claim that all generic drugs are equivalent to brand-name drugs.

1. The quality of generic drugs has attracted the attention of the U.S. military

It is no secret that the U.S. military does not trust the quality of generic drugs, and their disagreements and disagreements with the FDA over the quality control of generic drugs have long been made public. For example, many doctors have long warned that certain generic drugs of tacrolimus (tacrolimus) do not work well in the FDA. Tacrolimus is an immunosuppressive drug used to reduce the risk of rejection after allogeneic organ transplantation. However, it was found that some low-quality generic tacrolimus drugs may even cause kidney failure and seizures. Valisure, an independent laboratory commissioned by the U.S. military to test tacrolimus, found that the version produced by India's Intas Pharmaceuticals Ltd was not identical to its brand-name drug. The quality of Tacrolimus is just the tip of the iceberg of the crisis lurking beneath the surface. Miranda Janvrin, a researcher commissioned by the U.S. military, likened generic drugs to mimicking "deceased grandmother's baked cookies," with no recipe for the ingredients. The differences in the production process determine that there may be differences between generic drugs in terms of quality, including impurity components, content and release speed, and brand-name drugs that may lead to some serious consequences.

The U.S. military, trapped by inferior generics, is getting rid of the FDA and conducting a two-year quality review of 42 drugs, each made by multiple generic drug companies, with Valisure, an independent laboratory. The criteria for evaluating these different versions include potency and impurities. The military will use these results as a basis to screen for the highest quality generic drug manufacturers. While there is still a year to go before this project is completed, Valisure has clearly checked out a lot of issues. Valisure President David Light highlighted a disturbing outcome related to the high blood pressure, angina drug Metoprolol. For example, dissolution tests measure the extent and rate at which a solution is formed in dosage forms such as tablets, capsules, ointments, etc. The dissolution of a drug is very important for its bioavailability and therapeutic efficacy. Light said Valisure found that the actual dissolution difference between generic and brand-name drugs ranged from 4 to 53 percent. This means that those generics with dissolution differences above the threshold may not function as well as they should, and may even cause adverse effects.

The main disagreement between the FDA and the U.S. military is that the military expects the FDA to check the quality of generic drugs, while the FDA believes that their primary responsibility is to supervise manufacturing agencies, review their documentation and inspect factories, but not directly control the quality of products. FDA does not routinely test raw materials, drug substances, and finished drug products. During FDA inspections, they focus on compliance content rather than sampling and testing themselves. The website of the FDA's Office of Generics states that "all approved generics have the same high quality, strength, purity, and stability as brand-name formulations." It is on the basis of this assurance that drug wholesalers and pharmacy benefit managers (PBMs) in the United States are looking for generic drug manufacturers around the world that offer as low prices as possible. However, in the coming months, Valisure's data will come out, and the FDA's insistence that "all generics are of the same high quality" may become untenable. Valisure caused an uproar when he detected dimethylnitrosamine (NDMA) carcinogen in ranitidine.

2. The rise of generic drugs and regulatory rules

The boom and problems with generic drugs came after the Hatch Waxman Act was officially enacted. Previously, developers had to wait until the brand's patents had fully expired before they could test generic drugs, and they had to conduct clinical trials with similar safety and efficacy to the brand's drugs. It wasn't until the passage of the Hatch Waxman Act in 1984 that the aNDA application system and the concept of bioequivalence were created, greatly simplifying the process of bringing generic drugs to market. The Hatch Waxman Act also allows generics to begin the research process before the expiration of a brand-name drug patent, which could theoretically help a generic drug complete regulatory approval after the end of a brand-name drug patent.

In the process of approving generic drugs, the FDA usually focuses on bioequivalence (BE), therapeutic equivalence (TE), and pharmaceutical eqivalence (PE).

Bioequivalence (BE)

The goal of bioequivalence studies is whether a generic drug is similar to a reference listed drug (RLD) in the following ways:

• Rate and degree of absorption: Whether the two drugs are absorbed at the same rate and the total amount absorbed in the body.

• Area under the plasma concentration-time curve (AUC): A measure of the overall exposure of a drug in the body.

• Maximum blood concentration (Cmax): A measure of how high a drug is at its highest concentration.

• Time to Peak (Tmax): The time it takes for a drug to reach its maximum blood concentration.

There are a number of pharmacokinetic (PK) parameters that need to be evaluated in bioequivalence studies, including the maximum plasma concentration (Cmax) and AUC of the drug. FDA requires that the ratio and degree of bioequivalence must not be significantly different. Specifically, in these randomized cross-over trials, the PK value needed to fall between 80% and 125% of the RLD reference value, and the entire confidence interval (Cl) required for 90% of the PK value also had to fall between 80% and 125%. It is the latter condition that requires that the PK value of the generic drug must actually be very close to the RLD. According to the statistical standards required by the FDA, it is difficult for any generic drug to meet the CI requirements if the difference is more than 10%, and it is almost impossible to meet the CI requirements if the difference is close to 20%. According to the FDA, the gap between most generic drugs and RLD in PK parameters is within 4%.

Treatment Equivalence (TE)

Therapeutic equivalence is not only about the bioavailability of the drug (i.e., bioequivalence), but also about the actual clinical efficacy and safety of the drug. This means that the two drugs must be similar in the following ways:

• Therapeutic Effect: Produces the same efficacy in the treatment of the target disease.

• Safety: Same side effects and safety profile.

• Dosage and route of administration: used at the same dose and under the same route of administration.

Pharmaceutical Equivalence (PE)

Pharmaceutical equivalence is when two drugs are identical in the following ways:

• Active Ingredient: Contains the same active pharmaceutical ingredient.

• Dosage form: with the same dosage form, such as tablets, capsules, injections, etc.

• Route of administration: used through the same route of administration, such as oral, intravenous, topical, etc.

• Dose strength: Contains the same dose of the drug.

Pharmaceutical equivalence is one of the foundations for determining whether two drugs can be substituted for each other. Bioequivalence and therapeutic equivalence can only be further assessed on the basis of pharmaceutical equivalence.

3. The problem behind bioequivalence

The process of determining bioequivalence is considered by many to be the biggest source of problems with generic drugs. In its guidance on bioequivalence, the FDA requires the measurement of two parameters as a measure, Cmax and AUC, which must comply with the 80-125% rule and defines bioequivalence as "the delivery of the same amount of active ingredient into a patient's bloodstream in the same amount of time as an RLD." This creates the problem that there may be significant differences in the time it takes for drugs to be released and into the blood circulation and into the brain when Cmax and AUC are met, which may be one of the deep-seated reasons why many patients complain that "generic drugs are not as good as sugar pills". This is because the rate at which drugs enter the bloodstream is significantly associated with the management of certain indications, such as central nervous system stimulant drugs, such as attention deficit hyperactivity disorder (ADHD), narcolepsy, and certain types of depression.

For example, the inactive substance may not be the same between Wellbutrin XL, a brand name for ADHD, and its generic drug, Bupropion. While inactive ingredients do not affect the efficacy of the drug, they may cause different side effects. Another important difference is the SmartCoatTM technology. Wellbutrin XL uses this patented technology to achieve a stable release. However, Teva's release of a generic drug, Bupropion, sparked complaints almost immediately after it was launched in 2006, with patients saying they felt too excited or nervous after using the generic drug, and patients with depression felt their depression relapse quickly after taking the drug. The FDA then conducted an investigation and in 2012 asked Teva to conduct further bioequivalence studies. But Teva refused the FDA's request on the grounds that it could not recruit a sufficient number of patients, so in 2014 the FDA conducted its own bioequivalence tests and removed Teva's 300 mg Bupropion from shelves for more than a year, making it the first generic drug to be banned. FDA testing has shown that the PK index of generic drugs does not meet the conditions of 90% Cl and meets the conditions of 80-125% range, which is actually less than 75%. Therefore, the bioavailability is insufficient. Wellbutrin XL also uses a special SmartCoatTM to ensure a stable dose release. Generic drugs, on the other hand, do not use this technology, which leads to a rapid release, so patients feel the side effects of being too excited and nervous, and depressive symptoms quickly return.

The problem with generic drugs appears to be more pronounced in people with mental illness. Katherine Eban's book, "Bottle of Lies - The Inside Story of the Generic Drug Boom," exposes the issue of the extended-release antidepressant bupropion. Patients who were initially on stable medication began to experience suicidal ideation and other symptoms after switching to generics. After receiving multiple complaints over several years, the FDA withdrew several approved generic products from the market because further inspection found that these products were not being released at the same rate and extent as RLDs.

In addition, differences in excipients can also lead to differences between generic and brand-name drugs. The FDA allows different excipients to be used in generic drugs. For example, many medications may contain lactose or gluten, which can be problematic for those with lactose and gluten allergies.

4. Where is the road?

The purpose of this article is in no way to belittle the role and status of generic drugs. On the contrary, generic drugs, as the vast majority of drugs in the market, play an incomparable role in the health management of patients and the stability of the whole society. The generic drugs that are in question are only a small fraction. If you give a generic drug that is in question, then on the other hand, you can immediately come up with ten examples of effective generic drugs. The problem is that this small subset of generic drugs with quality defects has a negative impact on the patient population that distrusts the generic drugs and spreads them by word of mouth.

There is fierce competition in the generic drug market that is unimaginable to outsiders, and price advantage has become the headline survival method for many generic drug manufacturers. The problem is that today's pharmaceutical market doesn't always ensure that patients have access to safe and effective generics. And doctors caught between patients and suppliers are in an awkward position, unable to accurately judge the quality of generic drugs on their own. Because of this, people rely more on the quality control of generic drugs by regulatory agencies, and legislators to pursue advantages and avoid disadvantages from the perspective of legislation, give full play to the value of generic drugs, and avoid possible quality defects in this process.

Again, there is the issue of accountability. For the quality management of generic drugs, from the perspective of regulatory agencies, it is likely to fall into the situation of "leniency and severity without review". On the one hand, there is the quality of generic drugs, and on the other hand, there is a fragile supply chain. The slightest misalignment of this balance can be problematic. Statistically, this is a type I and type II error issue. Which is more serious, whether the innocent go to jail (type I error) or the guilty get away with punishment (type II error)? Putting generics with questionable quality on the market, while the supply chain problems appear to be temporarily resolved, actually have consequences that will ultimately create a larger supply crisis. The eventual delisting of a number of generic drugs is a case in point.

Pharmaceutical quality must be the responsibility of all participating organizations throughout the supply chain. Distributors, retail pharmacy chains, PBMs, and even payers all need to play a greater role in ensuring the quality of medicines. But the regulators are at the core, they are the only ones who decide which generics can be marketed, but there is no testing organization for this. This is why the U.S. military eventually had to find its own testing facility to confirm the quality of the drug.

The generic drug market is too important to the public, so everyone pays close attention to it.

Ref.

Edney, A. Generic Drug Quality Testing Gains Steam With Military Help. Bloomberg. 14. 05. 2024.

Kellermann, A. L. White House Plan To Curb Drug Shortages Doesn't Address Generics' Quality. Forbes. 24. 04. 2024.

Challenges In Ensuring The Quality Of Generic Medicines. Health Affairs. 2020. 39. https://doi.org/10.1377/hlthaff.2020.00321