When a drug comes first in the market the parent company can sell it exclusively under a brand name for a certain number of years. This time period depends on how many years left in the drug patent and the type of exclusivity granted and the time approved by the Food and Drug Administration (FDA). When the patent of exclusivity expires the other manufacturers can begin making the generic product. It is a common misconception that branded drugs are more effective than generic drugs. Misconception ranges from manufacturing standard that they are weaker to efficacy and just that drugs don’t work. The truth is both are similar.
The generic product is sometimes cheaper than the branded product. This is why some generic product gets a bad repo. There is a basic misperception that the generic products are not as good as the branded products because they are low priced. Before the company manufactures and market the generic drugs in the United States it must submit an Abbreviated New Drug Application or ANDA to the FDA. The application includes data proving the generic product is both pharmaceutically equivalent and bio equivalent to that of the branded product.
Pharmaceutical ingredients means the generic drugs contains the same drug compound as the innovator drug as well as having the same strength, the same route of administration, same dosage form and extent of absorption. To achieve bioequivalence the generic product must have the same effect as that of the brand drug. This means that the compound has the same action in the body in the same amount of time. This does not mean that they are same in every way and that is because of the excipients. Excipients are the inactive ingredients in a drug product, or the stuff that’s not the active drug molecule. Let’s say we take a 10 mg tablet of a popular allergy medication. If you weigh the tablet on a scale it will be definitely heavier than 10 mg that because 10 mg is relatively tiny. It is nearly impossible to make drug tablet so small. For eg a quarter table spoons of salt weighs around 1500 mg. 10 mg is less than10 grains of salt. Some drugs use less than 10 mg of active ingredients. Therefore the drug manufacturers will use approved compound to build up tablets such as lactose, starch, microcrystalline cellulose to bulk up tablets. Other excipients might help tablets disintegrate in the digestive tract, or provide flavoring and coloring and the list goes on. Generic and brand drugs will always have the same active ingredients but their excipients may vary. One or the other may have slightly more or fewer types of inactive ingredients depending on their manufacturing processes. The coloring agents usually also differ so that the products can distinguish themselves but even if the ingredients list may not be exactly the same between the brand and generic. The generic manufactures may still prove that their product is entirely bioequivalent if not then an adjustment to the excipients needs to be made.
In the late 1960’s an outbreak of intoxication occurred in Australia among patients taking the anticonvulsant drug phenytoin. In 87% of patients experiencing toxicity, drug levels measured in the blood were well beyond the therapeutic range, putting them at risk of side effects. Many patients had vomiting and other abnormalities and mental function. The good news was that majority of the people turned normal when the doze was reduced. But why were patient stable under any convulsive medication all of a sudden experiencing toxicity. It was because of the excipients. After evaluating the phenytoin capsules investigation discovered that in 1967 one manufacturer had changed its diluents, or bulking agent from calcium disulphate dehydrate to lactose. The lactose formulation allowed the phenytoin to dissolve more readily from the capsule, leading to higher concentrations in the blood. Thus some patients began to experience toxic side effects while others previously getting benefits from the phenytoin had their seizure control for the first time. This incident shows that the excipients are inert and justifies that they are so critical that the brand and generic are pharmaceutically equivalent and bioequivalent. Today all the regulatory body around the globe are really strict. They are not approving generic form of drug without a through scrutiny to the other factors. In addition to be pharmaceutically equivalent and bioequivalent generic drug must have same strength, identity, purity, quality as the branded product.
In 2008, a meta-analysis compared the clinical effectiveness of generic and brand name cardiovascular drugs. The study included 38 RCT’s (Randomised Control Trials) of 9 subclasses of cardiovascular medications, of which 38 (81%) were randomized controlled trials (RCTs). Clinical equivalence was noted in 7 of 7 RCTs (100%) of β-blockers, 10 of 11 RCTs (91%) of diuretics, 5 of 7 RCTs (71%) of calcium channel blockers, 3 of 3 RCTs (100%) of antiplatelet agents, 2 of 2 RCTs (100%) of statins, 1 of 1 RCT (100%) of angiotensin-converting enzyme inhibitors, and 1 of 1 RCT (100%) of α-blockers. Among narrow therapeutic index drugs, clinical equivalence was reported in 1 of 1 RCT (100%) of class 1 antiarrhythmic agents and 5 of 5 RCTs (100%) of warfarin. Aggregate effect size (n = 837) was −0.03 (95% confidence interval, −0.15 to 0.08), indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution.
Lets look deeper, some drugs have a narrow therapeutic index. The drug is only effective within a very small dosage range too little and the drug will have no effect, too much and the drug may cause harm. One such drug is a blood thinner Coumadin also known by its generic name Warfarin. Not everyone response to warfarin in the same way. So those taking it have their blood monitored regularly so that appropriate dose adjustment can be made because of which physicians and pharmacists are hesitant to interchange the brand and generic version of Coumadin and warfarin. Lets see what the data say.
A review article published in 2011 in the journal of pharmaceutical therapy. The review article examined 5 RCT’s and 6 observational studies comparing outcomes when switching patients from Coumadin to generic Warfarin. The observational studies suggest that those switching between brand to generic should be monitored more closely. So perhaps there are more reasons to be cautious about switching between brand and generic like warfarin. In the RCT’s there were no significant differences reported at all. No studies showed that the branded drug was more effective that the generic. Similar results were seen in systematic reviews of antiepileptic drugs. Even though national regulatory bodies require a mountain of data for proving bioequivalence, independent studies have shown the generics are just so effective. As innovator drugs there is still this lingering perception that among some practitioners that generic drugs aren’t as good.
A survey of 506 physicians in the US revealed that as many as 23% had negative opinions on the efficacy of generic drugs and those over the age of 55 years are 3 times likely to believe that. After a survey while 8-11% of doctors believe that generic drugs were less effective than the brand product and only 2.3% of pharmacists shared this opinion. Why is it so? Pharmacists spend a lot of time in school learning about the chemical nature in drugs and how excipients work in drug products perhaps resulting in a higher degree of confidence in well formulated generic drugs. Conversely, physicians are more likely to hear the firsthand account of the patients being unhappy with the generic making them less likely to prescribe in the future. Here are the consequences- a study compared adherence to statin therapies in patients that were started on either the brand or generic drug. A significantly higher number of patients started on the generic drugs, and those taking generics had an 8% reduction in hospitalization for acute coronary syndrome or stroke. Why, because generic cost less and people are more likely to stick to the stuff and is not as expensive for them. A chemical compound is a chemical compound and as long as bioequivalence is assured brand and generic drug should give the same result. There may be good reasons to be cautious to be switching back and forth between different formulations of certain narrow therapeutic index drugs but from vast majority of small molecular drugs there is no difference. We should not get hung upon the labels. The generic drug may appear different in terms of colour, flavor but the active ingredients is similar to that found in the branded drug. It is the active ingredient which will determine the effectiveness of the drug. The inactive ingredients will not affect the overall performance, safety & effectiveness of the generic drug. A generic drug is identical in strength, dosage form and mode of administration as of the branded drug. If the branded drug is a capsule the generic drug will also be in the form of a capsule. If the branded drug is taken orally then the generic drug will also be taken orally. A generic drug will have the same use indication as that of a branded drug. The generic drug is manufactured under the same strict standards and processes as that of a branded drug.
Branded drugs are more pricier because drug companies who have manufactured them have obtained drug patent which means no else in the market can produce or manufacture the drug until the patent expire which usually last between 17 to 20 years. Once the patent expires other companies can start selling the generic version of it at a lower price. Since generic need not need to manufacture from the start the cost of manufacturing of the drugs become significantly cheaper as they don’t need to pay for costly advertisement, marketing and promotion. Put into report generic drugs save consumers at an estimated $8 to $ 10 billion a year at rental pharmacies on average cost of the generic drugs is 80-85% lower than the branded drug. Generic drugs are safe effective and low cost. It is safe to transfer from branded drug to generic drug. Generic drug are allowed to have different filler materials and the active ingredient. That’s why generic drugs come in different shapes and sizes and colours compared to their brand name drug. So the problem is using different filler material and how the tablets gets dissolves and get absorbed in your body. So to overcome this problem the generic drug should be proven to have similar rate and extent of absorption as the branded drug before it gets approved.
For eg when we take a tablet it gets absorbed gradually and the concentration in the blood increases until it reaches a peak. Then it starts decreasing as the body starts metabolizing and getting rid of the drug. In clinical practice, the TI is the range of doses at which a medication appeared to be effective in clinical trials for a median of participants without unacceptable adverse effects. For most drugs, this range is wide enough, and the maximum plasma concentration of the drug (Cmax) and the area under the plasma concentration–time curve (AUC) achieved when the recommended doses of a drug are prescribed lie sufficiently above the minimum therapeutic concentration and sufficiently below the toxic concentration. So the generic drug company hire a group of people and gives them the drug being tested, then the blood samples are obtained from them to measure the concentration of the drug in the blood at various times. From these numbers an average Cmax an area under the curve are calculated and to ensure the precision of these numbers a 90% confidence interval is calculated. So the 90% confidence interval gives us a range which you were to repeat the same experiment there is a 90% chance that the average Cmax an AUC will lie within the range. The medical experts in the FDA specify that the 90% confidence interval of the Cmax and that of the AUC of the generic drug must be entirely within 80% to 125% of the average Cmax and AUC of the brand. If the confidence interval lies outside these ranges the generic drug will not be approved. Since the FDA allows little bit of room for variation. Concentration between brand name drug of the generic drug, does that mean they are different and we should switch between them. Well not quite, it depends on the therapeutic index of the drug in question.
TI = TD50/ED50
TD50à Dose that causes toxicity in half of the population
ED50 à dose that causes a desired response in half of the population
Therapeutic index is the ration between dose that causes toxicity and half of the population over the dose that causes a desired response in half of the population. A large therapeutic index implies that there is a wide range of concentration of drug and blood that would achieve the desired therapeutic effect and the small therapeutic index implies that there is a small range of concentration that achieve the desired therapeutic effect. So switching a drug with a small therapeutic index between brand and generic drugs is kind of risky because the new concentration might be outside the narrow range of desirable concentration. On the other hand switching the drug with a large therapeutic index is safe because even if the generic drug achieve a different concentration compared to the brand that concentration would still be within the desirable therapeutic range. The vast majority if drug have a large therapeutic index.
So switching between brands and generics is entirely safe and effective in those drugs. Switching is an issue in drugs with small therapeutic index. Brand name which is more expensive does not mean it is better.
North East Institute of Advanced Studies [NE-IAS]
Reference–Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease-A Systematic Review and Meta-analysis- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713758/