10/19 & 10/20: Bioequivalance
biosimilar
highly similar and with no clinically meaningful differences when compared to the reference product
Problem with off label uses for biosimilars
insurance tends to not cover off label uses, and the FDA can't approve the use of new medications when its still under patent
What makes demonstrating interchangeability difficult
manufacturers must take into account that patients who switched from 1 biosimilar to another might see different results
Determine the release mechanism: croscarmellose, ethylcellulose, microcrystalline cellulose
membrane controlled system
What kind of release mechanism does Klor-Con M10 use
membrane controlled system, starts dissolving within seconds since its not enterically coated or in a wax matrix
What kind of deviance is allowed for excipients of generics
must have identical stands of strength, quality, purity and identity, can differ in colors, flavors, and preservatives
Where do you find information on FDA therapeutic equivalence
orange book
What are the alternative to bioequivalence testing
pharmacodynamic testing and in vitro testing
What tests are used to determine bioavailability
plasma concentration, Tmax, AUC
can a bio similar be interchanged, or does it need to be prescribed every time
prescribed every time
What are the main differences between brand and generic drugs
price, insurance coverage, inactive ingredients, appearance
What database is used for finding biosimilars
purple book
What can be different between generics and brand names
shape, scoring, release mech, packaging, excipients, expiration date, and labeling(within certain limits)
What is the problem with using pharmacodynamic testing
some medications don't enter the blood stream
Who determines if something can be equivalent
state board
how is the orange book results demonstrated
table format
When are biosimilars prescribed for patients
tend to be used for those who had previously used the reference product (experienced) or those who haven't(naive) works for either
Reference product
the drug with original FDA approval, prescribed by provider
If you search a brand name drug in the orange book, what will you not find
the generics
Reference listed drug
the standard against which all generic drug products are compared
What can be altered as we look at the labels for the biosimilars
the testing conducted, difference in medicinal use, different labels
How is bio similar naming effective
used to track and remediate adverse effects, prevents inadvertent substitution, and allows for accurate product indentification
Determine the release mechanism: magnesium stearate, hydrogenated alcohol, PEG
wax matrix ER release form
What sort of things play into interpatient variability
weight, age, sex, race
What is the orange book website
www.fda.gov/cder/ob
Do two drugs being condsidered as generics need the same salt form? solution? ROA
yes to all three
What is the four criteria that must be hit for something to be considered a true generic
1. approved as safe and effective 2. pharmaceutically equivalent 3. bioequivalent 4. Adequately labeled 5. Follows GMP regulations
What is used to measure bioequivalence
Cmax, Tmax, AUC
What kind of release mechanism is used for Klor-Con
ER version that is contained in a wax matrix
What kind of generics are allowed to skip human trials due to unethical designations
IV solutions, its assumed that so long everything is the same there is no reason to undergo painful testing
Bioequivalence
The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
TE codes
Therapeutic equivalency
Bioequivalence criteria
Two drug products are deemed bioequivalent if the 90% confidence intervals of the geometric mean of the (generic/innovator) test ratio (Cmax or AUC) fall within the bioequivalence limits of 80-125%
Types of studies used for determining biosimilars
analytical studies, animal studies, clinical pharmacology studies, and additional clinical studies, can do pharmacokinetic studies
What type of average is used for the bioequivalence criteria
arithmetic mean, gets rid of outsliers
How can the purple book be searched
brand name or proper name
Can the RLD be brand or generic
brand only
What class of BCS drugs can be approved through in vitro testing alone in order to minimize the necessity for human testing
class 1
"A" rated drugs
considered therapeutically equivalent and may be interchanged
What does it mean to be pharmaceutically equivalent
contains identical amounts of the same active ingredient and in the identical dosage form and ROA
biosimilars (have/do not have) clinically meaningful differences from existing FDA approved biologics
do not have
What does it mean to be bioequivalent
does not present a known or potential bioequivalence problem or its meets an acceptable in vitro standard or if it does present such a known or potential problem, it is shown to meet appropriate stands
Can the RS be brand or generic
either
interchangeable product
highly similar with no clinically meaningful difference then compared to the reference product, the application includes additional data and information about the impact of switching or alternating between the product and reference product
Pharmaceutical equivalents must deliver (different/identical) amounts of the active ingredient over (different/identical) dosing period and they have (different/identical) inactive ingredients
identical, identical, different
"B" rated drugs
inadequate evidence of bioequivalence and should not be interchanged
How are biosimilars named
it takes the core name and then follows it with 4 RANDOM letters
How do bioequivalence criteria differ for drugs with Narrow TI
its much more strict since there is less room for error
What do biosimilars have in common with the reference product
living source, ROA, strength, dose, treatment benefits, potential side effects as reference product
Are generics always approved for the same use as brand name
no
Do generic products tend to be run in populations with the disease state
no
If a patient switches from one bio similar to another, should they be experiencing cross antigenicity
no
Do interchangeable products need prescriber approval to be changed
no, it goes through rigorous testing to prove similarity
Do generics need to go through all of the physical and biological trials that brand name medications need to go through to be approved for market
no, its assumed that if they are equivalent that they would do the same thing
Is it possible to have an AB2 or AB3 without AB1
no, its likely that the AB1 is no longer on the market
do large molecules have generics
no, they have biosimilars
What are the sources of variation in BE testing
normal vs. disease state interpatient variability content uniformity of dosage form release and subsequent absorption of drug and dosage form correlation of dissolution rate to absorption rate variability in experimental measurement for data
AP
parental equivalent
the way the purple book demonstrates its results stresses what main idea
that its more important to read the labels before determining anything since there are very few interchangeables
In addition to establishing biosimilarity, the manufacturer must demonstrate what to prove that it can be interchangeable
that switching between two products would not increase safety risk or decrease effectiveness
The reference product is similar to what
the RS or RLD of SMDs
How are biosimilars evaluated and approved by the FDA
the abbreviated pathway involves an extensive structural and functional comparison of the bio similar and reference product, all biologics are evaluated for their variations and how they are being controlled, FDA monitors all safety and effectiveness
Searching by what metric will bring up both the brand and generics in terms of equivalents
the active ingredient
Reference standard
the comparative product for TE testing
bioavailability
the rate and extend to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of drug action
What does an AB1 designation mean
there are multiple manufacturers of a certain dose, ROA, and MOA that are not all equivalent, the numbers help determine which ones are equivalent, AB1s are equivalent to each other, same all AB2s but AB1s are not equal to AB2
While there is a lot variability, most generic drugs when tested against the bioequivalence of the brand name tend to be what
they cluster close to 100%, there are not many outliers on the far end of the acceptable ranges
how is the purple book results demonstrated
tile formation
AT
topical equivalent