BIO 221
REGULATORY AFFAIRS COMPLIANCE IN
BIOMANUFACTURING
(3-3-4)
OFFICE COURSE
SESSION NUMBER
TITLE
1
2002 Safety Alert-Epogen (Epoetin alfa)
2
FDA Strengthens Safety Information for ErythropoiesisStimulating Agents (ESAs)
3
Violative Advertising and Promotional Labeling Letter
4
Completion of Investigational New Drug Application
(IND) Form
5
Heparin Mix-Up
6
Part 1: Abbreviated New Drug Applications (ANDA)
Part 2: FDA Public Health Advisory-ErythropoiesisStimulating Agents (ESAs)
7
Application to Market a Biologic
8
FDA Warning Letter: Example of Post-Marketing
Regulation
OFFICE EXERCISE 1
2002 Safety Alert-Epogen (Epoetin alfa)
Important Drug Warning
Counterfeiting of Epogen
Read the safety alert. Based on it, answer the following questions:
1. What is EPOGEN primarily used for?
2. Did the counterfeit vials examined by Amgen contain active ingredient? If so,
what was its concentration in relation to that expected for EPOGEN vials? What
is the actual concentration of active ingredient expected for EPOGEN vials?
3. Describe two features that could help in determining if the product possessed by
the health care professional is counterfeit.
4. If the health care professional has any product that is suspected to be counterfeit,
what is the instructed response?
OFFICE EXERCISE 2
FDA Strengthens Safety Information for Erythropoiesis-Stimulating Agents (ESAs)
Study the FDA news letter on erythropoiesis-stimulating agents. Based on the contents of
the letter answer the following questions:
1. What did the public health advisory, issued by the FDA on the day of the
letter, outline?
2. What are ESAs widely used for?
3. What are the names of the drugs, generic and brand names, affected by the
safety update?
4. ESAs are what forms of the naturally occurring human protein,
erythropoietin?
5. Natural erythropoietin is made by what organ?
6. What is the function of erythropoietin?
7. What have FDA and the manufacturer agreed on?
8. What does the new boxed warning advise physicians to do?
9. What risks are physicians and patients called on to weigh carefully?
10. From studies that had been recently completed, what was found in patients
with chronic renal failure when ESAs were given at higher than
recommended doses?
11. What was observed in other studies with patients having head and neck
cancers who received these higher doses?
12. In studies where ESAs were given at recommended doses what was
reported in patients with cancer who were not receiving chemotherapy?
13. With administration of ESAs at recommended doses what was observed in
patients following orthopedic surgery?
14. What was FDA then in the process of doing? In which month was the
safety of ESAs to be discussed and by which committee? What was a
possible outcome?
15. Had safety concerns from earlier ESA studies been previously discussed
by the above committee? If so, in what year?
16. In what years had product labeling been previously revised to reflect new
safety information?
17. Are ESAs approved for the treatment of the symptoms of anemia, such as
fatigue and shortness of breath, in cancer patients, surgical patients and
those with HIV?
OFFICE EXERCISE 3
Violative Advertising and Promotional Labeling Letter
Epoetin alfa, Procrit (Amgen, Inc)
Read the FDA letter on advertising and promotional labeling for a particular product.
Based on this letter:
1. Which Act and its implementing regulations have been violated?
2. Describe what makes promotional materials misleading in terms of 21 CFR §
202.1 (e)(6)(i).
3. Discuss all that is misleading about the company’s Cancer Management
Handbook advertisement which claims “With Procrit, help get his Hb BACK TO
NORMAL*.”
4. In the absence of data on a clinical benefit from attaining “normal” hemoglobin
(Hb) how must the company respond?
5. Describe what makes promotional materials false or misleading in terms of 21
CFR § 202.1 (e)(7)(i).
6. Of red blood cell transfusions and treatment with epoetin alfa, which provides for
the most rapid elevation in Hb levels in patients?
7. Had any patients who received epoietin alfa therapy in clinical trials also received
red blood cell transfusions? Explain why this could make misleading the
advertising claims made by the company on the effectiveness of Procrit on the Hb
response.
OFFICE EXERCISE 4
Completion of Investigational New Drug Application (IND) Form
You are the Senior Associate in the Regulatory Affairs Department of ABC Inc., a
prominent biotechnology company located at 1553 Long Road, Athens, Georgia 306051292. The company’s telephone number is (706) 355-5010. The company has been
developing a protein therapeutic with the generic name of protein kinase Z and trade
name PKZ. It is manufactured by expression of the gene for the human protein in
mammalian cells with use of recombinant DNA technology. You have compiled all the
items to go with the Investigational New Drug Application (IND) and today will be the
date of submission. You have been given the task of completing Form FDA 1571, i.e. the
IND form. Use the provided instructions “Filling out the Form FDA 1571” as a guide.
The dosage form in which the therapeutic is to be administered is injection. No previous
IND number has been assigned. The indication for the therapeutic is diabetes. Phase 1
clinical trials are to be conducted. No Investigational New Drug Applications, New Drug
or Antibiotic Applications, Drug Master Files and Product License Applications are
referred to in this application which is an initial IND. It is not a Sponsor-Investigator
IND. All the items in box 12 of the form, including an environmental assessment, have
been collated and will be included. The clinical study is to be conducted by a contract
research organization, but no sponsor obligations are to be transferred to this
organization. Catherine Jones MD is the person in ABC Inc. responsible for monitoring
the conduct and progress of the clinical investigations in addition to the review and
evaluation of information relevant to the safety of the drug. The name of the sponsor’s
authorized representative who will sign the form is James Latter.
OFFICE EXERCISE 5
Heparin Mix-Up
The following safety alert was posted by FDA on its MedWatch site.
Heparin Sodium Injection 10,000 units/mL, and HEP-LOCK U/P 10 units/mL
Medication Errors
Audience: Pharmacists, neonatology/pediatric healthcare professionals
[Posted 02/07/2007] Baxter and FDA notified healthcare professionals of
the potential for life threatening medication errors involving two Heparin
products, Heparin Sodium Injection 10,000 units/mL, and HEP-LOCK U/P
10 units/mL. Baxter is aware of fatal medication errors that have occurred
when two Heparin products with shades of blue labeling were mistaken for
each other. Three infant deaths resulted when the higher dosage Heparin
Sodium Injection 10,000 units/mL was inadvertently administered instead
of the lower dosage of HEP-LOCK U/P 10 units/mL. The currently
marketed 1 mL vials of both Heparin products use blue as the prominent
background color on their labels.
Read the Safety Alert issued by Baxter and the accompanying news article about a
product liability lawsuit against Baxter. Consider the following fictitious scenario.
Baxter’s attorney comes to your desk in the Office of Regulatory Affairs for Baxter. He
seems rather stressed. He asks if you could come up with reasons that Baxter had acted
appropriately when it first became aware of fatal medication errors with its heparin
products. He asked you if you could communicate them to him when they are ready. To
help clarify your thoughts on this matter you wrote down a list of questions:
1. Did Baxter address the issue when it first arose?
2. What were the five points that Baxter, in its safety alert of February 6 2007,
reminded healthcare professionals that they should do?
3. Does the labeling itself appear sufficiently clear to differentiate the two doses?
4. Was Baxter thinking of how the packaging and labels could be changed so as to
more readily distinguish the two products and reduce the risk of future medication
errors?
How would you answer these questions and why would you answer each of them that
way?
OFFICE EXERCISE 6
Part 1: Abbreviated New Drug Application (ANDA)
An Abbreviated New Drug Applications (ANDA) is used when a patent has expired, is
invalid, will not be infringed or does not exist, for a product that has been on the US
market and a company wishes to market a copy. In the US a drug patent lasts for 20
years,
An ANDA contains data which when submitted to FDA's Center for Drug Evaluation and
Research, Office of Generic Drugs, provides for the review and ultimate approval of a
generic drug product. Once approved, an applicant may manufacture and market the
generic drug product to provide a safe, effective and low cost alternative to the American
public.
A generic drug product is one that is comparable to an innovator drug product in dosage
form, strength, route of administration, quality, performance characteristics and intended
use. All approved products, both innovator and generic, are listed in FDA's Approved
Drug Products with Therapeutic Equivalence Evaluations (Orange Book).
Generic drug applications are termed "abbreviated" because they are generally not
required to include preclinical (animal) and clinical (human) data to establish safety and
effectiveness. Instead, generic applicants must scientifically demonstrate that their
product is bioequivalent (i.e., performs in the same manner as the innovator drug). One
way scientists demonstrate bioequivalence is to measure the time it takes the generic drug
to reach the bloodstream in 24 to 36 healthy volunteers. This gives them the rate of
absorption, or bioavailability, of the generic drug, which they can then compare to that of
the innovator drug. The generic version must deliver the same amount of active
ingredients into a patient's bloodstream in the same amount of time as the innovator
drug.
Using bioequivalence as the basis for approving generic copies of drug products was
established by the "Drug Price Competition and Patent Term Restoration Act of
1984," also known as the Waxman-Hatch Act. This Act expedites the availability of less
costly generic drugs by permitting FDA to approve applications to market generic
versions of brand-name drugs without conducting costly and duplicative clinical trials.
At the same time, the brand-name companies can apply for up to five additional years
longer patent protection for the new medicines they developed to make up for time lost
while their products were going through FDA's approval process. Brand-name drugs are
subject to the same bioequivalence tests as generics upon reformulation.
The required contents of an ANDA are set forth in section 505(j) of the Food, Drug and
Cosmetic Act (FDCA) and in agency regulations (21 CFR 314.94). The statute requires
that an ANDA contain:
a) Information showing that the proposed conditions of use for the drug have
previously been approved for a drug that is listed by FDA as approved for
safety and efficacy.
b) Proof that the active ingredient(s) are the same as in the listed drug.
c) Proof that the generic drug will use the same route of administration.
d) Proof that the generic drug is bioequivalent to the listed reference drug, i.e. its
rate and extent of absorption are not significantly different from the rate and
extent of absorption of the reference drug.
e) Information showing that the proposed generic labeling is the same as the
labeling approved for the listed drug, unless differences have been approved
in the light of safety and efficacy still being maintained.
f) The basic technical information required of a full NDA including a list of
components, statement of the composition of the drug, and description of the
methods and facilities used in the production of the drug.
g) Samples of the generic product and proposed labeling.
h) A patent certification informing FDA of the patent status of the listed
reference drug relied upon by the ANDA.
Answer the following questions:
1. The biotechnology company Alsoran Inc. sees a potentially lucrative market for
existin, a protein therapeutic currently marketed by Getahead Inc. under the brand
name of Fixup. Getahead has a valid patent, with another five years before
expiration, on this product. Should Alsoran submit an ANDA for existin?
2. What is the full name of the Congressional Act which allows for the use of
bioequivalence as a basis for approving generic copies of drug products?
3. Should samples of the generic product and proposed labeling be submitted with
an ANDA?
Part 2: FDA Public Health Advisory-Erythropoiesis-Stimulating Agents (ESAs)
Read the FDA Public Health Advisory on Erythropoiesis-Stimulating Agents (ESAs). On
the basis of this Advisory:
1. List three points that cancer patients currently using or considering the use of an
ESA should know.
2. List two points that patients with chronic kidney failure who are currently using
an ESA should know.
3. What evidence is there that ESAs lessen the symptoms of anemia, such as
fatigue?
OFFICE EXERCISE 7
Application to Market a Biologic
You are the Senior Associate in the Regulatory Affairs Department of ABC Inc., a
prominent biotechnology company located at 1553 Long Road, Athens, Georgia 306051292. The company’s telephone number is (706) 355-5010 and fax number is (706) 3536083. After a lot of dedicated work on the part of everyone concerned the company has
completed clinical trials with the protein therapeutic with the generic or established name
of protein kinase Z and trade name PKZ. The biochemical name is also protein kinase Z
There is no code name for it. It is manufactured by expression of the gene for the human
protein in mammalian cells with use of recombinant DNA technology. You have
compiled all the items to go with the Biologics License Application (BLA) and today will
be the date of submission. This is an original application that has never before been
submitted. You have been given the task of completing Form FDA 356h, i.e. the BLA
form. Use the accompanying “Instructions for Filling out Form FDA 356h” as a guide.
The dosage form in which the therapeutic is to be administered is injection. Its dosage
strengths range from 500 to 2000 International Units (IU). The route of administration is
subcutaneous. No previous Biologics License Application Number has been issued. The
indication for use of the therapeutic, proposed to be available by prescription, is diabetes.
The entire application, which is in paper format, will constitute three volumes. All
manufacturing steps, final dosage form and stability testing, packaging and control are to
be conducted at the same site as the company’s offices as addressed above with also the
same telephone number. There is no registration number for the site as yet and there is no
Drug Master File number. A contact at the site is the Director of Manufacturing, David B.
Smith PhD. The site is ready for inspection.
The Investigational New Drug Application (IND) which was submitted by the Company
with the assigned IND number of 22361 has been referenced in the current application.
All the items 1 through 19 listed on page 2 of the form, except for samples in the
chemistry section (item 4) since these were not requested by FDA, have been collated
and will be included in the application. There is no other information for item 20. For
item 2, final printed labeling is to be included. The name of the sponsor’s authorized
official who will sign the form is James Latter PhD. His address is that of the company
above and telephone number is (706) 355-5010 ext. 103.
OFFICE EXERCISE 8
FDA Warning Letter: Example of Post-Marketing Regulation
Under 21 CFR 314.81(b)(3)(i), sponsors of approved applications for marketed
prescription drugs and antibiotic drugs for human use are required to submit specimens of
promotional labeling and advertisements at the time of initial dissemination of the
labeling and at the time of initial publication of the advertisements. Each submission is
required to be accompanied by a completed transmittal Form FDA 2253 (Transmittal of
Advertisements and Promotional Labeling for Drugs and Biologics for Human Use).
Statutory authority for the collection of this information is provided by sections 505(a),
(b), (j), and (k) and 701(a) of the Federal Food, Drug, and Cosmetic Act. Similarly, under
21 CFR 601.12(f)(4), manufacturers of licensed biological products are required to
submit specimens of advertising and promotional labeling to FDA in accordance with 21
CFR 314.81(b)(3)(i). Statutory authority for the collection of this information is provided
by section 351 of the Public Health Service Act, which gives FDA the responsibility to
prescribe standards designed to ensure the safety, purity, potency, and effectiveness of
biological products. In furtherance of this responsibility, FDA regulates advertising and
labeling for biological products.
Read the warning letter provided to you. The company had submitted to FDA Form FDA
2253 together with new promotional materials to comply with the regulations as
described above. Answer the following questions:
1. Describe briefly why the promotional materials are false or misleading.
2. What is the response FDA has requested of the company?
3. How may FDA respond if the violations discussed in the letter are not corrected?