Generics Intro

Question 1

Patent Vs Data protection

Answer 1

Data protection will most likely expire before marketing excluvisity. Generics can begin being made but can’t be marketed until it’s over

Question 2

Types of Patent

Answer 2

Composition, Synthesis and Use. MAH can have all but often will have to negotiate with other companies for permission

Question 3

Composition Patent Outline

Answer 3

Compound structure (chemical shape)

Question 4

Synthesis Patent Outline

Answer 4

Chemical synthesis steps are patented

Question 5

Use Patent Outline

Answer 5

Covers clinical use of a compound (therapeutic target)

Question 6

Supplementary Protection Certificates

Answer 6

Adds 5 years of commercial patent protection

Question 7

EMA Data Excluvisity

Answer 7

8 (no generic applications filed) + 2 (data can be used to create generics but applications can’t be filed) + 1 (if originator has new indication)

Question 8

Generic Outline

Answer 8

Originator reaches end of patent. Manufacturers can produce bio-physically identical drugs that need pharmacology but not therapeutic conformity studies

Question 9

New Drug Application (NDA) Outline

Answer 9

Dossier submitted to FDA supporting novel drug approval process

Question 10

Abbreviated New Drug Application (ANDA) Outline

Answer 10

Application for generic drug that is supplemented by original NDA

Question 11

Hatch-Waxman Act (Drug Price Competition & Patent Restoration) Outline [US, 1984]

Answer 11

Encourages more ANDAs by providing incentives. Safe harbour, centralised ANDA path, provides 6 months exclusivity for 1st generic to market. Orange book (innovator benefits too: data exclusivity & extend patent)

Question 12

FDA Orange Book (Approved Drug Products w/ Therapeutic Equivalence Evaluations)

Answer 12

Lists all drugs that have been approved (safety & efficacy data). Lists patents to cover drugs

Question 13

4 ANDA Hatch-Waxman Application Routes

Answer 13

No pre-existing patents, Patent expiry, Waiting patent expiry and Invalid patents

Question 14

4 Types of Generics

Answer 14

Authorised, Branded, Unbranded and Super

Question 15

Authorised Genetics Outline

Answer 15

Innovator manufactured under original NDA. Can be sold before expiry, typically still expensive

Question 16

Branded Generic Outline

Answer 16

Approved under ANDA and marketed under trade name

Question 17

Unbranded Generic Outline

Answer 17

Approved under ANDA. Cheapest generic

Question 18

Super generics Outline

Answer 18

Same API but innovates formulation (eg dosage). Called Hybrid (EMA) or Complex (FDA)

Question 19

Bioequivilance Outline

Answer 19

No significant difference in API or active moiety. Demonstrated by comparing Cmax and AUC between 2 products (in crossover study). CI range should fall within 0.8-1.25 (exception highly variable drug)

Question 20

Highly Variable Drugs Outline

Answer 20

Drug’s intra-individual variation in 90% CI of >30%. CI range extended to 0.75-1.33. Assumes no significance for increased Cmax

Question 21

Therapeutic Index Calc

Answer 21

LD50/ED50 or TD50/ED50.> LD50 & <ED50 = narrow therapeutic index (less safe). <LD50 & >ED50 broader therapeutic index (more safe)

Question 22

Narrow Therapeutic Index

Answer 22

Therapeutic Index < 2. Unsafe

Question 23

Pharmaceutical Alternative Outline

Answer 23

Contain same active moiety as originator but differ in chemical form (salt/ester/ect) of API/Dosage form/Dosing (2 different salt forms are pharmaceutical alternatives)

Question 24

Pharmaceutical Equivalents Outline

Answer 24

Contain same APIs, dosage form and admin route with identical doses (can have different excipients)

Question 25

Therapeutic Equivalents Outline

Answer 25

Pharmaceutical equivalents with same clinical effect and safety profile when administered to patients when using conditions specified labelling

Question 26

Therapeutic Equivalence vs Bioequivalence

Answer 26

Different excipients in bioequivalence don't have therapeutic effect

Question 27

Bioequivalence Assumptions

Answer 27

Excipients are inert (no safety or efficacy impact), Salt forms are interchangable

Question 28

Biowaiver Outline [ICH M9]

Answer 28

Brings generics to market (if BCS 1 or 3 (clear dissolution profile)), without all bioequivalence studies. Dissolution studies main indication, excipients must be similar to originator. Doesn't apply: narrow TI, or modified release

Question 29

Dissolution Tests Outline

Answer 29

At pHs 1.2, 4.5 and 6.8 drugs must dissolve >85% in 30 minutes. 50-60% minimum acceptance similarity

Question 30

Salt Forms & Bioavailability

Answer 30

Salt form = increased solubility = increased dissolution = increased absorption

Question 31

Salt Form Toxicity

Answer 31

Salt forming agents can introduce contaminants. ICH MR(R2) describes salt form toxicology asssessment

Question 32

Excipient Contamination Risks

Answer 32

Interacts with API increasing degradation and forming novel (potentially toxic by-products)

Question 33

Gasping Syndrome Outline

Answer 33

Benzyl alcohol (bacteriostatic injection agent) when metabolic pathway is disrupted it builds and is lethal

Question 34

Biotechnology Variability

Answer 34

Glycosylation dependent on cell used to produce protein

Question 35

How to Fix Misfolded Aggregates

Answer 35

Preparation of inclusion bodies, dissolution of inclusion bodies, Refolding urea, soluble protein, rapid dilution (refolding)

Question 36

3 Stages Of Commercial Production

Answer 36

Upstream (liquid media prep, chemical hydrolysis), Bioreaction (biomass production, transformation), Downstream (solid-liquid, Adsorption, liquid-liquid extraction, distillation)

Question 37

Biosimilars vs Generics

Answer 37

Generics require identical API. Biosimilars can't be identical due to complexity of protein API (need to have similar activity and safety, necessary to perform clinical trials)