Post on 25-Aug-2020
Generic Drugs: What does equal really mean?
Dr. Peter J. Lin
Director Primary Care Initiatives
Canadian Heart Research Centre
Conflict Disclosure Information
FINANCIAL DISCLOSURE
Grants/Research Support: None
Speakers Bureau/Honoraria: Astrazeneca, Takeda, Boeringher
Ingelheim, Eli Lilly, Sanofi, Jansen
Merck, Pfizer, Servier , Abbott, Forest
Laboratories, Novartis, Purdue
Consulting Fees: None
Research Funding: None
Other: None
Speaker: Dr. Peter Lin
Title of Talk: Alzheimer’s Update
BRAND Name Generic?
Blue Cross Blue Shield of
Michigan Billboards
$20 million to test quality of Generics
Antihypertensive Agents Currently Available in Canada
ACE-Is
Benazepril
Captopril
Cilazapril
Enalapril
Fosinopril
Lisinopril
Perindopril
Quinapril
Ramipril
Trandolapril
ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker
Diuretics
Acetazolamide
Furosemide
Hydrochlorothiazide
Indapamide
Metolazone
Spironolactone
Triamterene
ARBs
Candesartan
Irbesartan
Losartan,
Olmesartan
Telmisartan
Valsartan
Beta-blockers
Acebutolol
Atenolol
Bisoprolol
Labetolol
Metoprolol
Nadolol
Pindolol
Propanolol
Timolol
CCBs
Amlodipine
Diltiazem
Felodipine
Nifedipine
Verapamil
Renin
inhibitors
Aliskiren
Snake-oil Salesman
•How
to
calm
kids
down.
Infants Relief
Chloroform
Cannabis
1962 Impala
FDA – Companies had to prove that a drug
was both safe and effective before it
reached the market place. All new drugs
had to go through a lengthy and expensive
process that included large-scale human
trials.
12
NDA
REVIEWERS
Chemist
Microbiologist
Pharmacologist
Biopharmaceutist
Clinician
Statistician
Compliance
(CMC)
Scientific
Investigations
Preclinical
Phase 1
Phase 2
Phase 3
Phase 4
Office Drug
Safety
Drug Advertising
Advisory
Committee
Searching for Molecules
Discovery
Safety Efficacy
Production
Sameness
Center for Drug Evaluation & Research
U.S. Food & Drug Administration 17
Hatch-Waxman Amendments to FFD&C Act - 1984
• Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities
• (do not have to repeat expensive clinical and pre-clinical trials)
Human bioequivalence studies have been
required for generic drugs since 1984
“Bioequivalence refers to the absence of a significant
difference in the rate at which or the extent to which
the active ingredient in pharmaceutical equivalents
becomes available at the site of drug action when two
drug products are administered under similar
experimental conditions in an appropriately designed
study.”
Welage LS et al. J Am Pharm Assn 2001;41(6):856-857 Abstract
Human bioequivalence studies have been
required for generic drugs since 1984
“Bioequivalence refers to the absence of a significant
difference in the rate at which or the extent to which
the active ingredient in pharmaceutical equivalents
becomes available at the site of drug action when two
drug products are administered under similar
experimental conditions in an appropriately designed
study.”
Welage LS et al. J Am Pharm Assn 2001;41(6):856-857 Abstract
Non-Inferiority Study
Center for Drug Evaluation & Research
U.S. Food & Drug Administration 20
What are the requirements for a generic drug?
• Same active ingredient(s)
• Same route of administration
• Same dosage form
• Same strength
• Same conditions of use
Compared to reference listed drug (RLD) - (brand name product)
Same ??
24
Bioequivalence Example
6 12 18 24 30 36 42 48 0
1
2
3
4
5
6
7
8 Test/Generic
Reference/Brand
25
Bioequivalence Example
6 12 18 24 30 36 42 48 0
1
2
3
4
5
6
7
8 Test/Generic
Reference/Brand
AUC
Bioequivalence
Source: Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part B: Oral Modified Release Formulations.
FDA “The relative mean measured AUC of the
modified-release formulation to the conventional
formulation should be between 80% and 125% in
the fasting state.”
What does Equal Mean?
80% 125%
-20% +25%
45% Window
What does Equal Mean?
80% 125%
-20% +25%
45% Window
How many people do you need to test?
12
FACT: Research shows that generics work just as well as
brand name drugs.
A recent study evaluated the results of 38 published clinical trials
that compared cardiovascular generic drugs to their brand-name
counterparts. There was no evidence that brand-name heart
drugs worked any better than generic heart drugs. [Kesselheim et
al. Clinical equivalence of generic and brand-name drugs used in
cardiovascular disease: a systematic review and meta-analysis.
JAMA. 2008;300(21)2514-2526].
Generic only 3% off
Looked at 8556 studies – only 47 matched criteria
Generic and Brand-Name Drugs Used in Cardiovascular Disease
30 Studies 837 Patients
28 per study
- 0.03
Fillers ???
Generic version almost doubles the inactive ingredients
Additional ingredients may increase the risk for allergic response and
pharmacists rarely caution patients against potential adversities and no
labeling is required. It is unclear how these ingredients will effect the
outcomes of the drug. Ex. sodium lauryl sulfate is (surfactant soap) that
can be used in a degreaser
Inactive Ingredients
Prinivil (Lisinopril) Merck & Co Inactive Ingredients in 20mg dose
1.Calcium Phosphate 4. Starch
2.Mannitol 5. Iron Oxide
3.Magnesium Sterate
Lisinoril by Mylan Inc. Generic Inactive ingredients in 20 mg dose
1.Collidal Sillicon Oxide 5. Providone
2.Croscarmellose sodium 6. pregelatinized starch
3.Diabasic calcium phosphate 7.Sodium lauryl sulfate
4.Mannitol 8.D&C Yellow #10 Aluminum lake HT
Generic version almost doubles the inactive ingredients
Additional ingredients may increase the risk for allergic response and
pharmacists rarely caution patients against potential adversities and no
labeling is required. It is unclear how these ingredients will effect the
outcomes of the drug. Ex. sodium lauryl sulfate is (surfactant soap) that
can be used in a degreaser
Inactive Ingredients
Prinivil (Lisinopril) Merck & Co Inactive Ingredients in 20mg dose
1.Calcium Phosphate 4. Starch
2.Mannitol 5. Iron Oxide
3.Magnesium Sterate
Lisinoril by Mylan Inc. Generic Inactive ingredients in 20 mg dose
1.Collidal Sillicon Oxide 5. Providone
2.Croscarmellose sodium 6. pregelatinized starch
3.Diabasic calcium phosphate 7.Sodium lauryl sulfate
4.Mannitol 8.D&C Yellow #10 Aluminum lake HT
Shelf Life
Ramipril vs 22 Generics
Ramipril vs 22 Generics
STABILITY: Metabolite Ramipril-diketopiperazine (DKP)
Clopidogrel 75mg
Clopidogrel 60mg good enough?
What about
eye drops?
ADD
Time (h)
Meth
ylp
hen
idate
(n
g/
mL)
Pharmacokinetic Profiles for MOH and OROS MPH
1OROS MPH (methylphenidate HCI) ER Tablets Citizen Petition. McNeil Consumer & Specialty Pharmaceuticals. 2004
UK Switch to Simvastatin
Phillips, Br J Cardiol 2007;14:280-5
Osteoporos Int (2012) 23:213–221
Osteoporos Int (2012) 23:213–221
Still on Therpary
Epilepsy – switch to Levetiracetam
November 1, 2008 all patients switched to generic
Retrospective Chart review 260 patients
105 patients Switched back (42.9%)
% Patients with Increased in seizure frequency: 19.6% vs 1.6% p<0.0001
Polytherapy: 3.225 (1.512-6.880) p<0.05
Epilepsia. 2011 Apr;52(4):810-5. doi: 10.1111/j.1528-1167.2011.03025.x. Epub 2011 Mar 22.
Hemorrhagic Events
Ann Pharmacother 2011;45:701-12
0 1 2
N=37,756 Brand only = 4468 1 Generic=20, 292 Switchers = 12,996
Thrombotic Events
Ann Pharmacother 2011;45:701-12
N=37,756 Brand only = 4468 1 Generic=20, 292 Switchers = 12,996
Center for Drug Evaluation & Research
U.S. Food & Drug Administration 57
Clinical/PD Dose-Response
Cli
nic
al/
PD
Res
pon
se
Log Dose
Government
“Because this company continued to violate current good
manufacturing practice regulations and falsify information on
drug applications, the FDA took these actions in an effort to
protect consumers,” said Dara Corrigan, FDA associate
commissioner for regulatory affairs.
Ranbaxy
May 15, 2013
http://features.blogs.fortune.cnn.com/2013/05/15/ranbaxy-fraud-lipitor/
1.Substitute Cheaper, Lower Quality
2.Substitute brand name drugs in lieu of their own
generics in bioequivalance tests to produce better
results
Patent Challenge
180 days exclusivity
(USA)
The lots of atorvastatin, packaged in bottles of 90
and 500 tablets, are being recalled due to
possible contamination with very small glass
particles similar to the size of a grain of sand
(less than 1 mm in size).
Alysena is produced in Spain by Laboratorios
Leon Farma and distributed in Canada by
Apotex. There have been growing concerns over
the quality and safety of drugs produced
overseas and many health advocates question
whether Health Canada is doing enough to
ensure overseas plants are following good
manufacturing practices.
Background
An inspection of a Pharmaceutical Factory in China was
conducted by the European Directorate for the Quality of
Medicines and Healthcare (EDQM) recently. During this
inspection, a concern was identified about possible
contamination of clindamycin with quetiapine. This
contamination may have resulted from trace amounts of
quetiapine on common equipment.
What should we do Today?
Think:
• Adherence?
• Drug working?
• Disease getting worse?
THE CANADIAN SIDE
Thanks for Staying Awake