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Totality of Evidence and 505(b)(2): Are Two Phase III Studies Too Many for a Well-Known Already-Approved Drug?

As the 505(b)(2) expert, Premier Consulting is exposed to many projects in which sponsors have attempted to leverage the 505(b)(2) pathway as a way to utilize information obtained from studies not conducted by or for the Sponsor. For the 505(b)(2) pathway, the strategic leveraging of all available data (e.g., “totality of the evidence”) helps to meet the NDA requirements through bridging to data in the published literature and/or the Agency’s previous findings of safety and efficacy of listed drug(s).

On July 27, Aradigm announced that they are hoping the FDA will look across the “totality of the evidence” in its recently submitted NDA through the 505(b)(2) regulatory pathway for Linhaliq (previously known as Pulmaquin), an inhaled formulation of the antibiotic ciprofloxacin for treatment of non-cystic fibrosis bronchiectasis (NCFBE) patients with chronic lung infections due to Pseudomonas aeruginosa (P. aeruginosa). NCFBE is characterized by irreversibly damaged and dilated bronchi with impaired mucociliary clearance that leads to recurrent bacterial infections.

The company’s July 27 announcement cited the FDA Modernization Act of 1997 (FDAMA), which allowed for approvals based on one pivotal trial plus confirmatory evidence and stated the NDA is “based on the positive Phase III pivotal clinical trial ARD-3150-1202 (ORBIT-4) and confirmatory evidence from Phase III study ARD-3150-1201 (ORBIT-3) and Phase 2b study ARD-3150-0902 (ORBIT-2), together with other supporting evidence from proprietary preclinical and clinical studies, as well as referencing other information about ciprofloxacin from publicly available sources”.

Aradigm is positioning that the “totality of the evidence”, as they found themselves holding a hand of cards that includes a mixed bag of results from two Phase III pivotal studies. You may be wondering, as this is a 505(b)(2) product, why were two Phase III studies conducted in the first place. We are, too.

Totality of Evidence

Let’s look at the history:  The effectiveness requirement for drug approval was added to the Federal Food, Drug, and Cosmetic Act (the Act or the FDC Act) in 1962. Between passage of the Act in 1938 and the 1962 amendments, drug manufacturers were required to show only that their drugs were safe. Congress adopted the 1962 Drug Amendments, which included a provision requiring manufacturers of drug products to establish a drug’s effectiveness by “substantial evidence” as defined in defined in Section 505(d) of the Act. Since the 1962 Amendments added this provision to the statute, discussions have ensued regarding the quantity and quality of the evidence needed to establish effectiveness. Section 505(d) of the Act uses the plural form in defining “substantial evidence” as “adequate and well-controlled investigations, including clinical investigations.”

In Section 115(a) of the Modernization Act (what Aradigm mentions in their recent press release), Congress amended Section 505(d) (21 U.S.C. 355(d)) of the Act to make it clear that the Agency may consider “based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation)” to constitute substantial evidence if the FDA determines that such data and evidence are sufficient to establish effectiveness.

Since that time, the FDA has relied on pertinent information from other adequate and well-controlled studies of a drug, such as studies of other doses and regimens, of other dosage forms, in other stages of disease, in other populations, and of different endpoints, to support a single adequate and well-controlled study demonstrating effectiveness of a new use. Although there is only one study of the exact new use, there are, in fact, confirmatory evidence from multiple studies supporting the new use, and expert judgment could conclude that the studies together represent substantial evidence of effectiveness. In other cases, the FDA has relied on only a single adequate and well-controlled efficacy study to support approval generally only in cases in which a single multicenter study of excellent design provided highly reliable and statistically strong evidence of an important clinical benefit.

FDA Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products provides insight into the concept of the totality-of-the-evidence approach (i.e., considerations of both the quantity and quality of the evidence to support effectiveness for drugs and biological products).

Active Pharmaceutical Ingredient, Dosage Form, and Route of Administration

Let’s take a moment to look at the active pharmaceutical ingredient (API), dosage form, and route of administration, indication, regulatory designations, and Aradigm’s drug development program.

First, the active pharmaceutical ingredient is Ciprofloxacin, an FDA-approved, widely prescribed broad-spectrum fluoroquinolone antibiotic available in oral and parenteral dosage forms for the treatment of exacerbations due to lower respiratory tract infections including P. aeruginosa. Linhaliq is a new formulation containing dual release ciprofloxacin for inhalation (DRCFI) entailing a mixture of liposomal and free ciprofloxacin. Inhaled antibiotics have advantages over oral and intravenous administration by delivering higher concentrations of the drug to the bronchi and by reducing systemic absorption and therefore side effects. Inhaled antibiotics might also afford a means to overcome bacterial resistance if the optimal dosing regimen is used.

Since ciprofloxacin is a previously approved product, this supports the 505(b)(2) regulatory pathway. Remember, as part of the 505(b)(2) application, any aspects of the proposed product that differ from the listed drug must be supported by adequate data and information to support the safety and effectiveness of the proposed product. The attributes that differ from the currently approved ciprofloxacin products (such as dosage form, route of administration) will require the submission of clinical data that may come from sponsor-conducted studies or publicly available information that the Sponsor can strategically bridge to.

Indication/ Regulatory Designations

The indication/patient population for Linhaliq is new – “treatment of NCFBE patients with chronic lung infections due to P. aeruginosa.”  NCFBE, an orphan population, is an unmet medical need with high morbidity and mortality with no currently approved treatment to prevent and reduce the number of pulmonary exacerbations (PE). Exacerbations of bronchiectasis have a major impact on quality of life, healthcare costs, and long-term risk of complications.

Aradigm has been granted orphan drug designations for inhaled liposomal ciprofloxacin as well as for inhaled free ciprofloxacin for non-CF bronchiectasis in the U.S. In 2014, Aradigm received fast track designation for Pulmaquin for NCFBE as well as Qualified Infectious Disease Product (QIDP) designated for the product.

In terms of expediting Linhaliq through the 505(b)(2) regulatory process – these designations help tremendously. They also suggest that there may be ways to streamline the development program.

As this indication is different from the currently approved ciprofloxacin products, efficacy and safety data will be necessary. But will the approval of Linhaliq require two (2) pivotal Phase III studies? Consideration of available information that supports the safety and efficacy of Linhaliq in this patient population is needed. It is clear that previous attempts to treat respiratory infections with inhaled antibiotics in NCFBE patients have failed due to poor respiratory tolerability – so a sufficient exposure/safety database will be important. Of course, safety and efficacy data of Linhaliq in NCFBE in a sponsor-conducted study is necessary, but support for the safety database can also come from data available in the published literature.

Linhaliq Development Program

Linhaliq has been extensively tested in nonclinical studies including a 2-year inhalation carcinogenicity study in rats that found no increase in tumors for rats receiving Linhaliq compared to the control group. A comprehensive program of phase I and II studies suggested optimal pharmacokinetic (PK) properties and microbiological efficacy of Linhaliq and dose to evaluate in the Phase 2b study. The Phase 2b study (ORBIT-2) was conducted in the United Kingdom in adult NCFBE patients in which Linhaliq, demonstrated microbiological efficacy without any evidence of tolerability or safety concerns. Although this microbiological efficacy was associated with positive effects upon PE outcome assessed for time to first exacerbation, it was statistically significant only in the per protocol population.

The Phase III clinical program consisted of two worldwide, double-blind, placebo-controlled pivotal trials (ORBIT-3 [NCT01515007] and ORBIT-4 [NCT02104245]) that were identical in design except that ORBIT-4 included a PK sub-study. In April 2014, Aradigm announced the dosing of the first patient in the ORBIT-3 clinical trial and announced the dosing of the first patient in the ORBIT-4 in June 2014.

As you can see, these two pivotal studies were conducted in parallel.

Each trial enrolled approximately 255 patients into a 48 week double-blind period consisting of 6 cycles of 28 days on treatment with Linhaliq or placebo plus 28 days off treatment, followed by a 28 day open label extension in which all participants received Pulmaquin (total treatment duration ~1 year). The superiority of Linhaliq vs. placebo during the double blind-period was evaluated in terms of the time to first primary endpoint (PE), whether mild, moderate, or severe PE, while key secondary endpoints included the reduction in the number of pulmonary exacerbations and improvements in the quality of life (QOL) measures. Lung function was monitored as a safety indicator.

The top-line results demonstrated that the primary endpoint was not statistically significant in ORBIT-3 but was statistically significant in ORBIT-4. Both studies showed statistically significant reduction in P. aeruginosa after 28 days. In ORBIT-3 and ORBIT-4, median time to first PE was 221 days and 230 days for Linhaliq, respectively, compared to 136 days and 163 days for placebo, respectively. Despite the similarity of the results, the increase was statistically significant only for ORBIT-4. Reduction in the frequency of PEs for the Linhaliq group over 48 weeks compared to the placebo group (secondary efficacy endpoint) was 13% in ORBIT-3 (not statistically significant) and 37% in ORBIT-4 (statistically significant). In both trials, there were no differences in lung function changes for the treatment groups, and the rate of treatment emergent adverse effects and deaths unrelated to treatment were similar for both Linhaliq and placebo groups.


One would question the decision to conduct two Phase III pivotal studies and clearly points out the risk of conducting these studies in parallel.

But, all is not lost, as Aradigm met twice with FDA to discuss the results, and it was decided to change the statistical analysis of the results from the pre-specified plan to stratification based on sex and the frequency of pulmonary exacerbations in the prior year.

Using the new stratification, ORBIT-4 again demonstrated a statistically significant increase in 72 days in the median time to first PE and a 37% reduction in the frequency of PEs over the 48-week treatment period. The new stratification did not, however, result in statistically significant findings in ORBIT-3.

Okay, now might be a good time for Aradigm to start panicking. Clearly, one would have to think based on the availability of data in the public domain to support the 505(b)(2) submission, the rare (orphan) patient population, unmet medical need with high morbidity and mortality with no currently approved treatment, that conducting two pivotal Phase III studies (disturbingly in parallel) may not have been necessary to meet regulatory requirements. We are unsure if any FDA early meetings (e.g., Pre-IND meetings) occurred in Linhaliq’s development.

Now that the studies are completed with contradictory results, the only option for Aradigm is to try to position the “totality of evidence” – that includes inconsistent results, post-hoc analyses, and inability to meet primary endpoints.

Based on the FDA’s high standards for the totality of evidence approach – it seems unlikely that the NDA will be approved without additional data. The Linhaliq NDA will likely have a January 2018 user fee goal, so we will have to wait until then to find out.

The Difference in an Early Strategic Approach

At Premier Consulting, we critically assess your 505(b)(2) product and identify early on aspects of the proposed product that differ from the listed drug that must be supported by adequate data and information to support the safety and effectiveness of the proposed product. Premier Consulting’s thorough research investigations allow the leveraging of the “totality of scientific evidence” up front during the development process, not at the NDA submission stage. We also identify early on potential variables that may confound study results and develop robust clinical drug development programs.

Lastly, we know the importance of obtaining early FDA concurrence on the entire drug development program via FDA meeting (e.g., Pre-IND meetings) is critical for success.

Premier Consulting has experienced great success when this “totality of scientific evidence” is strategically presented at these FDA meetings in a well-structured meeting package.

No one wants to end up in this situation. At the time of NDA submission, it is important to hold the correct cards in your hands, because once the cards are laid down, there is no picking them up! At Premier Consulting, we have experts available to discuss ways to strategically streamline your development program for the best regulatory and market outcomes. Contact us to learn more.


Stacey Ayres, PhD
Senior Director, Scientific and Regulatory Affairs