E-drug: E-DRUG: Re: Generics (contd)
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If the FDA has certified a generic as being bioequivalent to the originator
product then as far as I am aware there have not been any proven instances
where there has been an adverse patient outcome as the result of switching
from the brand to a generic. At times, there have been allegations of
problems associated with switching, but whenever these have been properly
investigated there has never been an substantiation of a problem. (One
caveat applies here and that is with regard to the excipients or the
so-called inactive ingredients in a drug. Besides having an active
ingredient solid drug forms e.g. capsules, tablets also contain filling
agents, stabilizers, colouring agents, etc. Generics may use different
excipients than the brand and sometimes patients can have adverse reactions
to the excipients from one particular product.) The problem that you may
be remembering was a bribery scandal involving some of the generic
companies and the FDA where FDA employees were paid to accelerate approval
of certain generic products. Even here, there was never any adverse
patient outcome. The lack of problems with bioequivalent generics extends
to the "Narrow Therapeutic Index" group of drugs. These are drugs where
the difference between a therapeutic concentration and a toxic
concentration is quite small. I have copied a letter from Stuart
Nightingale of the FDA about this issue which was posted on the FDA web
site in Jan. 1998.
Therapeutic Equivalence of Generic Drugs
Letter to Health Practitioners
January 28, 1998
Dear Colleague:
As you may be aware, certain individuals and groups have appeared recently
before state legislatures, state boards of pharmacy, and drug utilization
review committees, to express concerns about the interchangeability of
certain products they characterize as narrow therapeutic index (NTI) drug
products. A particular concern being raised by them is whether the safety
and efficacy profile of these products could change if a switch were made from a
brand-name product to an FDA-designated therapeutically equivalent generic
product. FDA wishes to comment on the issue of interchanging any brand-name
drug with a therapeutically equivalent generic drug and requests that you
inform your association's members of this information.
For both brand-name and generic drugs, FDA works with pharmaceutical
companies to assure that all drugs marketed in the U.S. meet specifications
for identity, strength, quality, purity and potency. In approving a generic
drug product, the FDA requires many rigorous tests and procedures to assure
that the generic drug is interchangeable with the brand-name drug under all
approved indications and conditions of use. For these reasons, FDA approved
product labeling does not recommend that any additional tests need to be
performed by the health care provider when a switch occurs from a
brand-name drug product to a generic equivalent drug product, from a
generic equivalent to a brand-name product drug, or from one generic
product to another when both are deemed equivalent to a brand-name drug
product. Brand-name drug products and therapeutically equivalent generic
drug products are identified in the FDA publication, "Approved Drug
Products with Therapeutic Equivalence Evaluations," frequently called the
"Orange Book."
In addition to tests performed prior to market entry, FDA regularly
assesses the quality of products in the marketplace and thoroughly
researches and evaluates reports of alleged drug product inequivalence. To
date, there are no documented examples of a generic product manufactured to
meet its approved specifications that could not be used interchangeably with the
corresponding brand-name drug. Questions have been raised in the past, as
well, regarding brand name and generic products about which there could be
concern that quality failures might represent a public safety hazard. FDA
has performed post-marketing testing on many of these drugs to assess their
quality. In one instance, more than 400 samples of 24 marketed brand-name
and generic drug products were tested and found to meet the established
standards of purity
and quality. Because patients may pay closer attention to their symptoms
when the substitution of one drug product for another occurs, an increase in
symptoms may be reported at that time, and anecdotal reports of decreased
efficacy or increased toxicity may result. Upon investigation by FDA, no
problems attributed to substitution of one approved drug product for another has
occurred.
FDA works with both brand-name and generic drug product manufacturers after
a drug product is in the marketplace to assure its quality. For example,
brand-name and generic drug product manufacturers may want to change the
drug formulation, site of manufacture, or manufacturing process after the drug
is in the marketplace. These types of changes can be put in place only
after the drug manufacturer provides the FDA with sufficient evidence that
the drug identity, strength, quality, purity and potency will not change.
There are products in which small changes in the dose and/or blood
concentration could potentially result in clinically important changes in
drug efficacy or safety. Usually, these drugs require frequent adjustments
in the dose of the drug and careful patient monitoring irrespective of
whether the drug is a brand or generic drug product. These drugs may
sometimes be described in FDA approved drug labeling as narrow therapeutic
range drugs.
FDA may recommend to the manufacturers additional tests for approval of
both brand-name and generic products, depending on the complexity of a drug
substance or drug product and also depending on whether small changes in
the dose and/or blood concentration could result in changes in drug
efficacy or safety. It may also require additional tests for certain
post-approval changes in manufacturing. The agency's recommendation to the
manufacturer for these additional tests is designed to give the practitioner
and patient additional assurance of product quality and interchangeability.
These
additional requirements should not be construed to mean that additional
clinical scrutiny is necessary when interchange occurs. If anything, the
additional tests required of pharmaceutical manufacturers are designed to
reduce, not increase, concerns on the part of patients and practitioners.
Based on FDA's determination of therapeutic equivalence between generic and
innovator drug products, the FDA concludes that:
Additional clinical tests or examinations by the health care provider are
not needed when a generic drug product is substituted for the brand-name
product.
Special precautions are not needed when a formulation and/or a
manufacturing change occurs for a drug product provided that the change is
approved according to applicable laws and regulations by the FDA. As noted
in the "Orange Book," in the judgment of the FDA, products evaluated as
therapeutically equivalent can be expected to have equivalent clinical
effect whether the product is brand name or generic drug product. It is not
necessary for the health care provider to approach any one therapeutic class
of drug products differently from any other class, when there has been a
determination of therapeutic equivalence by FDA for the drug products under
consideration.
In considering drug product selection decisions, FDA acknowledges and
supports the importance of good communication between the patient and the
health care provider, particularly with regard to medications that require
frequent monitoring of performance. We hope this information is useful to
health care providers when making decisions regarding drug product
selection. We thank you for seeing that this information reaches the
members of your organization.
Sincerely,
Stuart L. Nightingale, M.D.
Associate Commissioner for Health Affairs
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Joel Lexchin MD
121 Walmer Rd.
Toronto, Ontario
CANADA M5R 2X8
Phone: (416)-964-7186
Fax: (416)-923-9515
e mail: joel.lexchin@utoronto.ca
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