FDA officials offer advice on smooth BE studies, comparative analyses for combo products

To avoid clinical holds associated with bioequivalence (BE) and bioavailability (BA) studies for investigational new drug applications (BIO-INDs) for generic drugs, sponsors should follow recommendations in the Food and Drug Administration’s (FDA) product -specifics guidances (PSGs) and closely adhere to the reference listed drug (RLD) labeling, according to Andrea Dugas, a physician with the Division of Clinical Safety and Surveillance in the Office of Generic Drugs (OGD), who spoke at the 11 April Generic Drugs Forum.

At the meeting, FDA officials also imparted tips on ensuring the successful acceptance of a comparative analysis comparing a generic drug-device combination product to the RLD product.

According to Dugas, under 21 CFR 320.31, BA/BE studies are required to be submitted for approved drug products through an IND for products that are either radioactively labeled, cytotoxic or have a dosage that is higher than the maximum single or total daily dose specified in the RLD labeling.

The most common reason cited by Dugas for why the agency issues a clinical hold for these studies is that the formulation would subject human subjects to an unreasonable and significant risk of illness or injury. Another primary reason is the clinical investigator is not qualified to lead an investigation. According to Dugas, this is “easily avoidable” and is due to the sponsor forgetting to file the investigator’s CV and can be easily remedied once this is submitted.

Other top reasons are the Investigators Brochure contains “misleading or erroneous or incomplete” information. This too can be remedied by the sponsor’s submission of a complete and accurate brochure; another reason is the study does not contain sufficient information to assess the risk of safety in subjects, which can also be corrected by submitting a complete study protocol.

“If you submit those three things, the CV, and the Investigator’s Brochure and a complete study protocol you will narrow this down to the main reason we put these studies on clinical hold and this is because of a significant risk of injury to patients,” said Dugas.

To avoid problems, sponsors should follow recommendation in FDA’s PSGs and refer to the RLD labeling. These let sponsors know “who should not be receiving the drug and potential drug interactions, and if a drug is contraindicated for patients with thyroid disease, make sure that patients with thyroid disease is excluded” from these studies.

In addition, she said the PSGs “offer tips on study designs.”

Dugas also recommended that sponsors should avoid saying they are enrolling patients with normal vital health signs, which is very vague, “Instead of saying normal vital signs, what is considered normal?” Instead, sponsors should submit specific values defining normal vital health signs.

Submitting comparative analyses

Separately, Shabnam Foroughi, a physician with OGD’s Division of Clinical Review, described the methods that sponsors should use to support comparative analysis for drug-device combination products filed as ANDAs. Products in this category include injectables, such as prefilled syringes, which represent 38% of products, followed by oral combination products, topical vaginal and rectal products, and ophthalmic drugs.

To support these studies sponsors should do a physical comparison and ensure the visual, auditory, tactile features of the proposed generic are comparable to the RLD, including the size, shape, and color of the proposed generic.

If there are minor differences, explain how the difference will not affect the user’s interface with the device and its safe use. For example, if sponsors use a different color in a plunger rod for a prefilled syringe, they should demonstrate the color is not critical to the correct use of the device. If FDA agrees that the design difference is a minor design difference, it will consider this an acceptable change, said Foroughi.

Sponsors should also conduct a labeling comparison and ensure that the labeling and the instructions for use are similar to the RLD labeling. Generally, the generic drug product labeling must be the same as the RLD, yet there are certain limited exceptions which can be made on a case-by-case basis.

Some advice for comparative analysis is to engage with FDA during product development through controlled correspondence and provide specific questions in the pre-ANDA request.

Generic Drugs Forum

FDA officials offer advice on smooth BE studies, comparative analyses for combo products

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