SILVER SPRING, MD 12 August 2011—Advisers to FDA overwhelmingly supported the agency’s first steps toward establishing new standards to assess the bioequivalence of generic and innovator drugs that have what is known as a narrow therapeutic index (NTI).
During a July 26 meeting in Silver Spring, Maryland, members of FDA’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology showed unanimous or near-unanimous support for a proposed definition of NTI drugs, new statistical methods to determine bioequivalence, and the tightening of standards for determining drug potency.
According to FDA’s proposed definition, NTI drugs are those "where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions." By serious, FDA means that the adverse reaction is "persistent, irreversible, slowly reversible, or life-threatening."
The proposed definition also requires that NTI drugs have steep dose–response curves for safety and efficacy when used at normal doses and dosing intervals; that patients taking the drugs generally require therapeutic monitoring of pharmacodynamic or pharmacokinetic measures; and that drug concentrations in study volunteers show little within-subject variability.
"The definition is not perfect, but we believe it will allow us to move forward," said Lawrence Yu, deputy director for science and chemistry at FDA’s Office of Generic Drugs.
FDA’s current method for assessing bioequivalence requires that, for any generic drug product, the average peak plasma, serum, or blood concentration (Cmax) and the average area under the concentration-versus-time curve (AUC) for the drug must fall within 80–125% of the Cmax and AUC values of the innovator drug product.
The agency has not developed a list of NTI drugs, and committee members were not asked at the meeting for input on which drugs should appear on such a list.
Advisory committee members last year recommended narrowing the 80–125% range for NTI drugs (see June 1, 2010, AJHP News). FDA staff at the recent meeting presented statistical simulations comparing the current standard against tighter bioequivalency ranges and showing how changes to the standard would affect the likelihood that a comparator drug would be found bioequivalent to the innovator drug.
Barbara Davit, an acting division director in FDA’s Office of Generic Drugs, recommended that, for innovator drugs whose Cmax and AUC values show <10% variability within test subjects, the bioequivalence limits for generics should be within 90–111.11%. For innovator drugs whose Cmax and AUC values vary by more than 10%, the bioequivalence limits should be wider than 90–111.11% but no greater than 80–125%.
"We believe that this approach to bioequivalence encourages the development of low-variability formulations," Davit said.
The advisers were not asked to vote on the proposed limits, but, instead, on whether to support changes in the bioequivalence testing procedures that would require the recruitment of additional study participants. In all, 12 of the 13 advisers supported these changes.
FDA officials said that the agency will mull the advice it received during the meeting and solicit public comments on any proposed changes to the agency’s assessment of NTI drugs.
Why it matters. The question of whether generic drugs perform as well as innovator products is important to patients who may unknowingly receive one in place of the other, said James Hennessey, associate professor of medicine at Beth Israel Deaconess Medical Center in Boston.
Hennessey, speaking at the meeting on behalf of the American Thyroid Association and other endocrine groups, said levothyroxine sodium products that are bioequivalent by FDA’s current standards are not necessarily interchangeable.
Within FDA’s allowed bioequivalency range, he said, supposedly identical doses of different levothyroxine sodium products can actually be dissimilar enough to affect the amount of drug needed for an optimal patient response.
Hennessey and others last year published the results of a study based on a survey of frequent prescribers of levothyroxine sodium. Of 199 adverse events reported by survey recipients, 177 had followed a change in the product supplied to the patient by the pharmacy, Henessey said. Of the 54 serious adverse events, 52 occurred after the patient was switched to a different manufacturer’s levothyroxine sodium product. Nearly all substitutions were made without the prescriber’s prior knowledge, Hennessey said.
He said manufacturers of levothyroxine sodium have made great progress toward reducing the variability of their products, so that patients who are stabilized on one brand and dosage usually have a consistent response to that medication.
Other public speakers at the meeting raised concerns about switching among brand-name and generic antiseizure drugs and medications used by liver or kidney transplant recipients. The speakers asked FDA to ensure that these drugs are placed on the NTI drug list.
Hennessey said he was "very reassured" by what he had seen that day about FDA’s stance toward NTI drugs.
But FDA adviser Arthur Kibbe, professor of pharmaceutical sciences at Wilkes University in Wilkes-Barre, Pennsylvania, said he was concerned that FDA’s proposed NTI drug requirements would not apply to the already marketed drugs cited by the public speakers.
"We’re going to vote on something that will increase the cost of the next [generic drug] applications, and yet I fear the problems are with what’s on the marketplace right now," he said.
Potency testing. The tightening of potency standards for NTI drugs could, however, have an effect on both existing and new products.
Potency refers to the amount of active ingredient per dosage unit. Potency testing is done before product lots are released to the market and periodically afterward to ensure that the material remains within specifications through its expiration date.
FDA pharmacologist Wenlie Jiang said the most frequent reason for the recall of an NTI drug is that it is found to be subpotent or superpotent.
Jiang said that if bioequivalency limits are tightened for NTI drugs, assay limits for potency testing should likewise be narrowed to improve the consistency and safety of these drugs.
Most potency tests currently have assay limits of 90–110% of the reference value, according to FDA.
Jiang said the 90–110% range is insufficient for NTI drugs with close dose strengths, because allowable losses of potency can cause the drug content to overlap with the next-lower dose strength.
All 13 voting advisers agreed with FDA’s proposal to tighten the potency assay standard for NTI drugs to 95.0–105.0% of the reference value.