Many fixed-dose drug-drug combination products arise from an observation that a synergistic effect occurs when two drugs are administered together, or that both drugs are frequently taken together for convenience. As one or both drugs are typically already approved, the 505(b)(2) pathway is the obvious choice for approval of many drug-drug combination products. We want to discuss a question that we are frequently asked by Sponsors: are Phase 2 and 3 studies necessary for fixed-combination drug products seeking approval via the 505(b)(2) pathway?

It would make sense to think that with two drug products already approved by the FDA that fewer Phase 2 and 3 studies should be required when applied in combination. But this is not always the case. In fact, fixed-combination drug-drug products sometimes require more studies than single component products.

Fixed-Combination Drug-Drug Products

Take the example of Allergan Inc. and AstraZeneca PLC working together to develop a combination aztreonam and avibactam product. The double-antibiotic product makes sense. Aztreonam is unique amongst β-lactam antibiotics in that it is resistant to hydrolysis by some metallo-β-lactamases (Amber Class B), yet it is inactive against isolates that produce other serine β-lactamases (Amber Class A and C). Avibactrim, a non-β-lactam β-lactamase inhibitor, restores aztreonam’s activity against isolates expressing multiple β-lactamases. As most Enterobacteriaceae isolates that produce metallo-β-lactamases increasingly coproduce class A or class C β-lactamases, the aztreonam and -avibactam products are already being employed to combat these antibiotic resistant pathogens. Funding support for the Phase 2 and 3 studies will be provided by the US government’s Biomedical Advanced Research and Development Authority and the European Union’s Innovative Medicines Initiative.

Another example is the combination of naltrexone HCl and bupropion HCl (Contrave^® NDA205777, Purdue Pharma LP) for weight management. In this case, the constituent’s drugs come from 2 different pharmacological classes: naltrexone is an opioid antagonist, and bupropion is an inhibitor of the neuronal reuptake of dopamine and norepinephrine. Together they are believed to affect the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The combination of both products results in a synergistic effect on weight loss.

In both of these examples, each of the constituent drugs had already been approved by the FDA, but the combination of the two drugs had not. However, in both cases, the FDA required at least one Phase 2 and one Phase 3 study. In fact, for the approval of Contrave, the development program required 4 x Phase 2 studies, and 4 x Phase 3 studies in 4,500 subjects, in addition to a nonclinical safety pharmacology study.

Of the 93 drug-drug combination products in Premier Consulting’s proprietary 505(b)(2) database for which approval data are available, two-thirds (63/93) required at least one Phase 2 or 3 study, and 28 required more than 4 Phase 2/3 studies. Of the remaining 30 studies, a further 6 studies required nonclinical studies leaving a total of 69/93 (68%) requiring studies for approval.

Why are so many studies required if both drugs are already approved?

The Combination Rule

In many cases, additional studies beyond those required for the original approvals of the 2 component drugs are required because the FDA must apply what is commonly referred to as the combination rule (21 CFR Section 300.50: Fixed-combination Prescription Drugs for Humans). This regulation states that “Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.” Two ‘special cases’ of the rule are listed: for the addition of a component that enhances the safety and efficacy of the principal active, and to minimize the potential for abuse of the active.

Recent proposed changes to the regulation include:

1. a clarification that the Combination Rule will apply to co-packaged and over-the-counter monograph drugs as well as prescription. (The FDA currently applies a similar standard under 21CFR 330.10(a)(4)(iv) in the development of OTC monographs, and has already been applying the Combination Rule to co-packaged products)
2. a provision for the FDA to grant a waiver of some or all of the requirements in cases where it would be infeasible or medically unreasonable or unethical to meet the requirements, or for natural-sourced drugs/products in which the components make up the combination product, and
3. removal of the exception for DESI¹ drugs that are awaiting the results of safety and efficacy evaluations

These changes are more about harmonizing the existing language between product classes, and won’t make much difference to most Sponsors. In fact, the FDA has determined that this proposed rule is not a significant regulatory action.

What Are the Practical Implications of the Combination Rule?

In order to fulfill the requirements of the Combination Rule, a combination must demonstrate that each component contributes to the safety or efficacy of the product. This typically requires a multi-factorial study in which each component is compared separately and in combination to a placebo control. For example, if the product aims to combine Drug A and Drug B, 2 clinical studies with the following treatment arms may be required to demonstrate that each component contributes to the overall effect of the drug:

1. Placebo
2. Drug A
3. Drug B
4. Drug A and Drug B combined

Developing a triple drug combination product may require 8 treatment arms! However, the complexity increases even more when one considers that the dose of each drug must be justified in terms of dosing frequency, amount of each drug, and duration of each effect. If the dosage requires clinical justification, the required studies may be so numerous or large they may not be logistically or financially feasible.

Which Studies Should Your Development Plan Include?

When planning a development program for a combination product, it pays to have a 505(b)(2) expert on your side to minimize the size and scope of studies required and to apply 505(b)(2) pathway-specific strategic knowledge for FDA feedback at the Pre-IND stage and beyond.

Prior experience in working with the 505(b)(2) regulatory pathway facilitates the use of appropriate data from the literature, product labels, and OTC monographs to reduce the clinical requirements for approval of the final combination product.

To learn more about ways Premier Consulting’s multi-disciplinary team can help you get your product approved with a minimal development program, read more here or contact us.

Author:

Angela Drew, Ph.D.
Product Ideation Consultant

¹DESI = Drug Efficacy Study Implementation. ‘DESI drugs’ approved between 1938 and 1962 were only evaluated for safety under the FD&C Act. In response to the Kefauver-Harris Drug Amendments to the FD&C Act, FDA initiated DESI reviews to assess the efficacy of these drugs. The National Academy of Sciences-National Research Council produced the reports for evaluation by the FDA. A significant number of the drugs undergoing DESI review were fixed-combination drugs.