This new series will discuss some public ideas about mental health and mental illness that may not be firmly grounded in fact or supported by specialists. There are many options to discuss, some more essential for people to know about than others, and I thought we’d begin with a very important one – whether generic medications are just as effective as their brand name (BN) parents, or whether, due to design or to sloppy or unethical manufacturing practices, they often don’t work.
This is an important matter for all of medicine, but certainly an issue in Psychiatry and for the public. In 2019, over 17% of US adults took prescription medication to help with mental problems.[1] We hope, of course, that all of these medications were accurately prescribed (the majority are not given by specialists) and that they were able to help people desperate for relief. Some problems can be treated without medication, but there are those that cannot be. For people with these problems, psychiatric medication can literally be a lifesaver.
Since the price of many BN medications is high to patients and third party payors, reaching $993 per capita in the US in 2019,[2] businesses and governments have tried to lower the expense by providing medications similar to BN products after the original patents expire. Given the extreme cost of developing new medications and getting a successful one through the approval process, $2.6 billion,[3] innovators bringing new treatment tools to the market are protected for a period of twenty years. This is intended to allow them to recoup their investment and make an adequate profit for their investors, thereby providing incentive for new drug development (which many providers and patients greatly appreciate). Sometimes governments will step in and support development for treatments that the market will not support; many countries ensure the availability of routine vaccines this way.[4]
Once the patent on a BN medication expires, other pharmaceutical companies may apply to the government (e.g., the FDA in the US) for approval of a preparation that they can sell at lower cost, while still making a profit. There are many steps to work through to make sure that 1) the new preparation works as well as the parent, and 2) the newly formulated medicine is as safe as the original. The process for the FDA, for example, has evolved over decades as it struggles to protect consumers and treat manufacturers fairly. If you really want to know how the sausage is made, so to speak, there are several excellent broad and technical descriptions to delve into.[5],[6] For todays’ discussion, let’s highlight the key differences currently allowed between BN and generic medications and how well they appear to be adhered to.
Bioavailability (BA) is the fraction of a medicine that reaches systemic circulation (i.e., the blood stream). The relative BA of a drug given orally, for example, is compared to the absolute BA when given intravenously (IV), which is always 100%. Relative BA is affected not only by the chemical components of a drug, but also by factors that may affect its absorption. This may include the method of delivery (oral, injection, skin patch), the state of the drug (solid, liquid, suspension), the size of the particles, the local pH, and whether another medication or food is being taken at the same time. Generic preparations do not always have the same chemical makeup as the parent: they should contain the same active ingredient, but may have different binders or dyes. Some generic preparations also deliver medication in different ways, such as immediate release versus slow or extended release.
At one time, the FDA simply and arbitrarily allowed the BA of a proposed generic version to range from 80-120% of the parent medication. This effectively allowed a 40% swing in BA: for each generic manufacturer, the effective dose of their product might be too high (101-120%) or too low (80-99%) to be well tolerated or even work. Clinicians trying to sustain an effective response to a medication would sometimes be confused each time the pharmacy substituted a generic from a new manufacturer, a switch largely unnoticed by patients and even some providers. The BA of generic versions was not readily available to pharmacists, providers or patients, so substitution was effectively blind, and still is commonly based on cost.
Consider a patient being changed from BN version for which an ideal dose, balancing benefit and side effects, has been determined and accepted by doctor and patient. The first generic substitution might carry a BA at 80% of the original, essentially 4/5 of the determined effective dose. This might well lower the benefit of the medication, prompting the provider to raise the dose she prescribed, restoring the effective blood level; as a result, the patient and prescriber are pleased. The next month or so, though, another generic brand is substituted and its BA is 120% of the original brand. The dose had just been raised to compensate for a lower amount in the first generic and now a second, with an effectively higher amount of the drug, is being taken at a dose that would have been too high for the brand name version. The new BA is now over 120% of the level desired by the patient and doctor for the original BN prescription, and this often adds to side effects or toxicities. The same problem could occur when the patient was initially stabilized on a generic from a particular manufacturer, as all versions vary, and these changes in BA may also affect the levels of other medications in patients’ bodies.
For this reason, in 1992 the FDA changed to using a narrower bioequivalence (BE) standard. With all of the variances in composition and delivery method, the generic manufacturer must convince the governing body that their new product will deliver the same active ingredient at the same levels in the blood for the same amount of time. For approval, these measurements must fall within 80-125% of BN preparations with only 5% statistical error. If it is not feasible to demonstrate this, more indirect measures, such as comparisons of outcome efficacy, may be substituted. Though it may not sound like it, these are more stringent criteria.[7]
This amount of change may still be noticeable clinically, however, and represents the only best possible situation. Due to the worldwide location of many generic manufacturers, monitoring is often not feasible, and there have been many cases of generic manufacturers not adhering to these standards. In her book Bottle of Lies: The Inside Story of the Generic Drug Boom,[8] Katherine Eban describes examples of unethical generic manufactures eluding FDA control. Recent calls for greater international oversight, updated standards, and greater transparency would allow clinicians increased knowledge about the quality and effectiveness of generic medications.[9]
So what is the answer? Are generics just as good as BN? The answer is maybe: the buyer (and prescriber) must beware. Hopefully, your provider is alert to as many risks as he can be aware of and works closely with pharmacies to monitor changes and quality in generic brands. Any change in treatment outcome, including increases or decreases in side effects, may be a signal that BA or BE has changed and efforts should then be made to determine whether this is linked to a substitution in generic manufacturer. Sometimes, due to the purchase of one brand by another, even this is difficult to assess. Though the odds are that most generic substitutions should not be much of a problem, remaining alert to the possibility that the amount of medication you are receiving might have changed when you receive a new refill is unfortunately necessary.
Our next post will address whether or not people with mental illnesses are more violent than those without.
[1] Mental Health Treatment Among Adults: United States, 2019. National Center for Health Statistics. Center for Disease Control web site. Published September 2020. Available at https://www.cdc.gov/nchs/products/databriefs/db380.htm. Accessed March 16, 2023. [2] How Much Does The United States Spend On Prescription Drugs Compared To Other Countries? Peter G. Peterson Foundation web site. Published November 7, 2022. Available at https://www.pgpf.org/blog/2022/11/how-much-does-the-united-states-spend-on-prescription-drugs-compared-to-other-countries. Accessed March 16. 2023. [3] Sullivan T: A Tough Road: Cost To Develop One New Drug Is $2.6 Billion; Approval Rate for Drugs Entering Clinical Development is Less Than 12%. Policy and Medicine web site. Updated March 21, 2019. Available at https://www.policymed.com/2014/12/a-tough-road-cost-to-develop-one-new-drug-is-26-billion-approval-rate-for-drugs-entering-clinical-de.html. Accessed March 16, 2023. [4] The U.S. Government & Gavi, the Vaccine Alliance. Global Helath Policy, Kaiser Family Foundation web site. Published March 7. 2023. Available at https://www.kff.org/global-health-policy/fact-sheet/the-u-s-government-gavi-the-vaccine-alliance/. Accessed March 17, 2023. [5] Bioavailability Studies Submitted in NDAs or INDs — General Considerations; Guidance for Industry. FDA (Food and Drug Administration) web site. US Department of Health and Human Services. Published April 2022. Available at https://www.fda.gov/media/121311/download. Accessed March 10, 2023. [6] Beers DO, Karst KR: Generic and innovator drugs: a guide to FDA approval requirements, 8th Edition. New York, Wolters Kluwer; 2020. [7] Andrade C: Bioequivalence of generic drugs: a simple explanation for a US Food and Drug Administration requirement. J Clin Psychiatry 76(6):e742-e744, 2015 [8] Eban K: Bottle of Lies: The Inside Story of the Generic Drug Boom. New York, HarperCollins, 2019 [9] Bate R, Mathur A, Lever H, et al: Generics Substitution, Bioequivalence Standards, and International Oversight: Complex Issues Facing the FDA. Trends in Pharmacological Sciences 37(3):184-191, 2016