Legal and Ethical Issues in Veterinary Pharmaceuticals

Legal and Ethical Issues in Veterinary Pharmaceuticals

Loading
Loading Social Plug-ins...
Language: English
Save to myLibrary Download PDF
Go to Page # Page of 85

Description: Manufacturing and compounding issues in Equine Pharmaceuticals are discussed. Maintaining the integrity, potency and quality of compounded products is examined. Other topics covered include available pharmaceuticals, “pioneer” pharmaceuticals, what is required by the FDA, generics, compounded drugs, and concerns.

 
Author: Scott D. Stanley, Ph.D., Professor (Fellow) | Visits: 4039 | Page Views: 4205
Domain:  Medicine Category: Veterinary Subcategory: Pharmaceuticals 
Upload Date:
Short URL: http://www.wesrch.com/medical/pdfME19LMO31UNBJ
Loading
Loading...



px *        px *

* Default width and height in pixels. Change it to your required dimensions.

 
Contents:
Legal and Ethical Veterinary Compounding
Scott D. Stanley, Ph.D., Professor University of California, Davis School of Veterinary Medicine
American Association of Equine Practitioners 2009

Equine Chemistry Research
Serum fentanyl concentration (ng/ml)

Drug Detection Determination, Identification, Confirmation

100

Pharmacokinetics
10

T1/2, AUC, Cl Metabolite ID

1

0.1

Proteomics
Cl OH H2N Cl C C H H H CH3 N C CH3 H CH3
100 95 90 85 80 75 1302.4410 70 65 17+ 60 55 50 45 40 35 1230.2482 30 25 18+ 20 15 10 5 0

0

1

2

3 Time (h)

4

5

6

Erythropoietin, Growth Hormone, Cobratoxin
1476.0369

15+
1383.7832

Clenbuterol m/z 240

16+
1581.2524

14+

1703.0424

13+

1250 1300 1350 1400 American Association 1450 Equine Practitioner 2009 of 1500 1550 1600 1650 1700

Horse Industry Integrity
Industry Integrity (Perception) High Profile Events
Triple Crown Breeder's Cup

Trainer's Livelihood
Disqualification Suspension Fine

Laboratory Reputation
American Association of Equine Practitioner 2009

Magical Effects of Drugs/Medications
Irish mythology: Salmon of knowledge Victorian mythology: Alice in Wonderland American mythology: Popeye and spinach Greek mythology: Diomedes and his mares

American Association of Equine Practitioner 2009

Equine Pharmaceuticals:
Manufacturing/
Compounding Issues
AAEP 2009

Definitions
Integrity � means retention of potency until
"beyond use date"

Potency � means active ingredient strength
within �10% of the labeled amount

Quality � means the absence of harmful levels
of contaminants including filthy, putrid or decomposed substances and absence of active ingredients other than those noted on the label
American Association of Equine Practitioner 2009

Compounded Products
The original Food Drug and Cosmetic Act passed 100 years ago was passed because:
At the time almost all drugs available were compounded by pharmacists There were no standards to insure quality and purity There were no standards for efficacy and safety

American Association of Equine Practitioner 2009

Available Pharmaceuticals
FDA-Approved "Pioneer" Drugs
For use in the horse For use in other animals For human use

Generic Drugs Compounded Drugs

American Association of Equine Practitioner 2009

"Pioneer" Pharmaceuticals FDA approval process:
Dosage Efficacy Safety Withdrawal Times
(food animals)

Stability Labeling Packaging Advertising Adverse Events

Manufacturing
American Association of Equine Practitioner 2009

FDA Approved Drugs: What is Required?
Drug Efficacy must be demonstrated in two well-controlled trials one of which must be in clinical cases. Drug Safety must be demonstrated in one or more studies in the target species
acute toxicity study sub-acute toxicity study field safety studies
American Association of Equine Practitioner 2009

FDA Approved Drugs: What is Required?
Manufacturing:
All raw materials for drug manufacture must be obtained from an FDA approved source The manufacturing procedure must be described in detail and meet the rigorous standards of FDA's Good Manufacturing Practices (GMP) Stringent testing standards for drug potency and purity must be established
American Association of Equine Practitioner 2009

FDA Approved Drugs: What is Required?
Manufacturing:
Stability data must be generated in order to establish the expiration dating Detailed records of each batch of drug produced must be maintained Representative samples of each batch of drugs must be retained for future testing FDA regularly inspects manufacturing facilities
American Association of Equine Practitioner 2009

What is a Generic Drug?
A generic drug is an exact copy of an FDA approved drug that is no longer patent protected. All generic drugs are approved by FDA Additional efficacy and safety data may be required (e.g., field safety)

American Association of Equine Practitioner 2009

"Generic" Pharmaceuticals
FDA approval process:
Bioequivalence (and/or) Chemical Equivalence Manufacturing Packaging Labeling
American Association of Equine Practitioner 2009

What is a Generic Drug?
The requirements for FDA approved raw material sources are the same for a generic drug All GMP requirements apply to generic drugs All annual reporting requirements are the same as for original drugs

American Association of Equine Practitioner 2009

Compounding Pharmacies
Are a necessary and beneficial component of veterinary practice Compounded drugs...
are not FDA-approved are not generic drugs
American Association of Equine Practitioner 2009

Compounded Drugs
Pharmacy compounding of veterinary drugs has exploded in the past few years Allows for DVMs to have formulated
Drugs no longer commercially available Drugs not available on animal health market Reformulate drugs into suitable dosage forms

American Association of Equine Practitioner 2009

Compounded Drugs
No regulations on raw material sources No quality standards No stability data requisite Supposed to be a prescription for a specific need in a specific animal (VCPR) Bulk compounding is not legal

American Association of Equine Practitioner 2009

Compounded Drugs
It is illegal to compound a specific product when there is an approved drug form of that specific product except to make a different dosing form. However, the approved product must be used to make the compounded new dose form. It is illegal to mark up prices on compounded drugs
American Association of Equine Practitioner 2009

Compounded Drugs
If you use a compounded product, you assume liability for any adverse effects or efficacy failure Drug manufacturers are required to carry product liability insurance Pharmacies are not required to carry product liability insurance
American Association of Equine Practitioner 2009

Compounded Drugs
It is illegal to place expiration dating on compounded drug beyond 180 days from preparation It is illegal to have a drug compounded in order to obtain the drug at a lower price Compounded products are not "generic" forms of approved drug products!

American Association of Equine Practitioner 2009

Veterinary Practitioners...

. . . are put in a position of evaluating the integrity of the compounding pharmacy as well as the quality and consistency of the pharmaceuticals they produce!

American Association of Equine Practitioner 2009

Concerns:
Efficacy Quality
Potency Purity

Consistency Liability
American Association of Equine Practitioner 2009

Compounded Drugs
Little or no ongoing external oversight of:
Consistency Quality Potency Bioavailability Sterility Stability Safety Labeling Advertising Adverse Events

Mainly self-regulated
American Association of Equine Practitioner 2009

Questions you may want to ask:
Who is doing the compounding?
Often a technician with minimal training

Where were they trained?
Pharmacists - little training in compounding; No training in manufacturing

Do they use pharmaceutical grade chemicals?
Drug companies will not supply Chemicals bought through sources like PCCA are questionable, often produced overseas (e.g., China)
American Association of Equine Practitioner 2009

Compounding of Animal Drugs
>12,000 compounding pharmacies in the United States
Most compound veterinary products Many market on the internet

Big profits to be made
Estimated $300 million annually Comprises >20% of animal pharmaceutical industry
American Association of Equine Practitioner 2009

Compounding Pharmacy "Best Practices"
California Pharmacy Board

American Association of Equine Practitioners 2009

Compounding by Licensed Pharmacies
Compounding means work is done under the supervision of a licensed pharmacist.
Altering dose form or delivery system Altering the strength of a drug Combining components Preparing a drug product from raw chemicals

Compounding, does not include, preparation a compounded drug product that is available commercially.
American Association of Equine Practitioner 2009

Limitations and Requirements
No product should be compounded prior to receipt of a valid prescription A pharmacy may store a limited quantity of a compounded drug in advance.

American Association of Equine Practitioner 2009

Limitations and Requirements
A "reasonable quantity" of compounded drug product may be furnished to be prescriber for office use.
is sufficient for admin. to patients in the prescriber's office or for distribution of not more than a 72-hr supply to the prescriber's patients.

American Association of Equine Practitioner 2009

Master Formula Record
Active ingredients to be used Inactive ingredients to be used Procedure to be used to prepare the drug Quality reviews required at each step in preparation of the drug Post compounding process Expiry dating requirements
American Association of Equine Practitioner 2009

Limitation and Requirements
Where a pharmacy does not routinely compound a particular drug product, the master formula record for that product may be recorded on the prescription document itself. "This may have prevented the incident in Palm Beach, Florida."
American Association of Equine Practitioner 2009

Limitation and Requirements
The Pharmacist performing or supervising compounding is responsible for the integrity, potency, quality, and labeled strength of a compounded drug product until it is dispensed.

American Association of Equine Practitioner 2009

Limitation and Requirements
Every compounded drug product shall be given an use by date representing the date beyond which, in the professional judgement of the pharmacist, it should not be used. The date shall not exceed 180 days from preparation.

American Association of Equine Practitioner 2009

Records of Compounded Drug Products
The master formula record The date the drug product was compounded The identity of the personnel who compounded the drug product The identity of the pharmacist reviewing the final drug product The quantity of each component used
American Association of Equine Practitioner 2009

Comparison for pharmaceutical equivalence of FDA-approved products and compounded preparations of Ketoprofen, Amikacin, and Boldenone
AAEP 2009

Illegal Veterinary Compounding

American Association of Equine Practitioner 2009

Product Potency
Ketoprofen (Ketofen�) � stated concentration for all products was 100 mg/ml Amikacin (Amiglyde-V�) � stated concentration for all products was 250 mg/ml Boldenone (Equipoise�) � stated concentration for was 50 mg/ml for 5 of 6 products tested and 25 mg/ml for the final product

American Association of Equine Practitioner 2009

Ketoprofen Potency:
120 Ketofen� (100 mg/mL) Compounder (100 mg/mL)

Ketoprofen Concentration (mg/mL)

100

80

60

40

20

0 1 2 A B C D E F I J L M

American Association of Pharmacy Equine Practitioner 2009

Amikacin Potency:
350 Amiglyde-V� (250 mg/mL) Compounder (250 mg/mL)

Amikacin Concentration (mg/mL)

300 250 200 150 100 50 0 1 A B E F H K L

American Association of Equine Practitioner 2009 Pharmacy

Boldenone Potency:
Equipoise� (50 mg/ml) Compounder (50 mg/ml) Compounder (25 mg/ml)

50

Boldenone concentration (mg/ml)

40

30

20

10

0 1 C E F L G

American AssociationPharmacy Practitioner 2009 of Equine

Product Purity
FDA Criteria for product purity
shall not exceed 2.0 total percentage impurity shall not exceed 0.1 percentage single impurity

American Association of Equine Practitioner 2009

Amikacin Purity:
2.5 Amiglyde-V� (250 mg/ml) Compounder (250 mg/ml) 2.0

% Total Impurities

1.5

1.0

0.5

0.0 2 A B C D E F G

American Association of Equine Practitioner 2009 Pharmacy

Boldenone Purity:
5 Equipoise� (50 mg/mL) Compounder (50 mg/mL) Compounder (25 mg/mL) 4

% Total Impurities

3

2

1

0 1 C E F L G

American Association of EquinePharmacy 2009 Practitioner

Medical Therapy for Equine Joint Disease: Understanding your Choices?
AAEP 2009

Medical Therapies for Equine Joint Disease
FDA Approved Animal Drugs FDA Approved Generic Drugs Compounded Products Off-Label Use of Medical Devices as Drugs

American Association of Equine Practitioner 2009

FDA Approved Drugs For Equine Joint Disease
NSAIDs
Phenylbutazone, flunixin, ketoprofen, diclofenac

Corticosteroids
Methylprednisolone acetate, triamcinolone acetonide, dexamethasone

Hyaluronic acid
Hylartin-V, Hyvisc, Hylovet, Legend

PSGAG (Adequan)
American Association of Equine Practitioner 2009

Generic Drugs for Equine Joint Disease:
Phenybutazone Flunixin Methylprednisolone acetate Dexamethasone SP

American Association of Equine Practitioner 2009

What is not a Generic Drug
Compounded Products
HA solutions Glucosamine Injection Cocktails (HA, Glucosamine, Chondroitin)

Medical devices used off label as drugs
MAP-5 and Chondroprotec

American Association of Equine Practitioner 2009

Well Controlled Study
Blinded: The person making observations is not aware of treatment group assignment Randomized: The subjects are randomly assigned to treatment group Standardized: All subjects are treated exactly the same (exercise, feeding, other drugs, etc). The only difference between groups is test drug(s)

American Association of Equine Practitioner 2009

Uncontrolled Studies
Testimonials and uncontrolled studies are especially poor indicators for efficacy
Rest and concurrent therapy are usually not controlled The use of other physical and medical therapies are often confounding factors Judgement of efficacy is biased

American Association of Equine Practitioner 2009

Compounded Drugs
Common products compounded for equine joint disease
betamethasone suspension acetyl-d-glucosamine injection HA injection "cocktail injections" containing glucosamine, HA and chondroitin

American Association of Equine Practitioner 2009

Medical Devices
There are medical devices for the veterinary field that are being sold and promoted illegally for off-label use to treat equine DJD
MAP-5 is an HA solution labeled as a cryopreservative for semen Chondroprotec is a solution of chondroitin sulfate labeled as a topical for wound healing
American Association of Equine Practitioner 2009

Medical Devices
MAP-5 is not a "generic" form of Legend! Chondroprotec is not a "generic" form of Adequan! The AAEP has taken the position that it is unethical for a DVM to tell a client that one of these medical devices or a compounded drug is a "generic" form of an FDA approved drug
American Association of Equine Practitioner 2009

Legal Implications
A legal expert at the AAEP Convention in New Orleans in 2003 warned:
A client cannot consent to substandard practice The fact that the use of compounded drug or the off label use of medical devices is common practice will not constitute a viable defense in a malpractice suit

American Association of Equine Practitioner 2009

Veterinarians are Liable!
No Malpractice Coverage
"There would be an exclusion in a veterinarian's malpractice insurance nullifying coverage if the practitioner were engaged in an illegal act, such as the use of a compounded pharmaceuticals from bulk drugs." AVMA
American Association of Equine Practitioner 2009

Palm Beach Polo Ponies

American Association of Equine Practitioner 2009

� Biodyl

(Merial)
0.05 g 100 mg 1,000 g 1,500 g 100 ml

Each 100 ml contains:
Cyanocobalamin (Vitamin B12) Sodium Selenite Potassium aspartate semihydrate Magnesium aspartate tetrahydrate Excipient q.s.

American Association of Equine Practitioner 2009

Compounded Formulation
Each 100 ml contains:
Cyanocobalamin (Vitamin B12) Sodium Selenite Potassium aspartate semihydrate Magnesium aspartate tetrahydrate Excipient q.s. 0.05 g ????? mg 1,000 g 1,500 g 100 ml

American Association of Equine Practitioner 2009

Selenium Toxicity

American Association of Equine Practitioner 2009

American Association of Equine Practitioner 2009

American Association of Equine Practitioner 2009

American Association of Equine Practitioner 2009

American Association of Equine Practitioner 2009

American Association of Equine Practitioner 2009

"Just like Ventipulmin but cheaper"

American Association of Equine Practitioner 2009

FDA Warning Letters

American Association of Equine Practitioner 2009

FDA Warning Letters

American Association of Equine Practitioner 2009

American Association of Equine Practitioner 2009

American Association of Equine Practitioner 2009

Illegal Veterinary Compounding

The compounding pharmacy advised that Mixture #1 was proprietary formulation.
American Association of Equine Practitioner 2009

Illegal Veterinary Compounding

The compounding pharmacy advised that Mixture #5 was the same as Mixture #1 with an additional active ingredient. (Salmeterol)
American Association of Equine Practitioner 2009

Unknown Compounds

American Association of Equine Practitioner 2009

Ketoprofen Gel

American Association of Equine Practitioner 2009

Ketoprofen Paste

American Association of Equine Practitioner 2009

Clenbuterol Solution

American Association of Equine Practitioner 2009

Anabolic Steroids

American Association of Equine Practitioner 2009

Glycine-Proline-Glutamate

GPE is the N-terminal tripeptide of insulinlike growth factor-1 and has been shown to be neuroprotective following ischemia-induced brain injury.
American Association of Equine Practitioner 2009

Flunixin Injection

Flunixin analysis determined concentration was only 68% of the label claimed potency!

American Association of Equine Practitioner 2009

Omeprazole Powder

Omeprazole powder analysis determined concentration was only 78% of the label claimed potency!

American Association of Equine Practitioner 2009

Phenylbutazone Powder

Phenylbutazone powder analysis determined concentration was only 72% of the label claimed potency!
American Association of Equine Practitioner 2009

Illegal Veterinary Compounding

Modafinil is used treatment of narcolepsy . Modafinil has received some publicity in the past when several athletes were discovered allegedly using it as a performance-enhancing doping agent. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant.
American Association of Equine Practitioner 2009

Industry Concerns:
Major source of new medications for veterinary medicine are diminishing Drug discovery is very expensive Most veterinary drugs have come via parent company human research initiatives More pharmaceutical companies have consolidated and their animal health divisions could be sold or eliminated if they are profitable
American Association of Equine Practitioner 2009

Recommendations:
Use FDA approved products when available Use a compounding pharmacist that follows FDA Guidelines for Good Compounding Practices and has product liability insurance Use compounded products only for individual animals
American Association of Equine Practitioner 2009

Recommendations:
Avoid off label use of devices as drugs Do not tell a your clients that a device or a compounded drug is a "generic" form of an approved FDA product!

American Association of Equine Practitioner 2009

Subscribe
x