December 1, 2010 (Vol. 30, No. 21)

Prabhavathi Fernandes, Ph.D.

Regulatory Hurdles Are Higher, but a New Well-Defined Path Means We Know How High to Jump

Antibiotic development has become a challenging therapeutic area. Shifting and evolving regulatory guidelines have made design of clinical trials difficult and the prospect for marketing approval fairly low. In addition, the short-term treatment regimens have made the sector relatively unattractive from a return on investment perspective, particularly for antibiotics targeting relatively simple community-acquired infections.

This has led to reduced investment in antibiotic drug development despite the continued and growing need for novel  antibiotics. These challenges, as well as evolving antibiotic stewardship and generic competition, have led to new approaches for the clinical development of antibiotics used for community-acquired infections.

Prabhavathi Fernandes, Ph.D.

An important period of antibiotic development occurred from the 1980s to the mid-1990s. During this period, new antibiotics were tested in vitro for spectrum of activity, potency, and resistance development. Animal models provided proof of concept for efficacy because it was understood that they were a reliable predictor of human efficacy.

Antibiotics were developed for the organ of interest or site of infection such as the respiratory tract, urinary tract, and bloodstream infections. Simple or uncomplicated infections such as sinusitis or minor abscesses were initially studied to determine safety, efficacy, and the dose to be used in Phase III studies in which more serious or complicated infections were included.

Antibiotics, when approved, were marketed widely for both uncomplicated, which made up the bulk of the sales, and complicated infections. Unfortunately, the widespread use of antibiotics in humans, particularly for minor infections or for respiratory viral infections, resulted in high antibiotic resistance rates.

From 2000 to 2010, safety issues increased regulatory oversight. Unlike most other classes of drugs, antibiotics are used for short durations and safety had a lower regulatory hurdle than chronically administered drugs during that time period. In the early 2000s, antibiotics, once approved, were generally considered safe for widespread use. This changed with the postmarketing toxicity-related failures of temafloxacin, trovafloxacin, and telithromycin (Ketek™). The Ketek case led to Congressional hearings, changes at the FDA, and an era of regulatory conservativeness in antibiotic evaluation and approval.

In the mid-2000s, because of increased regulatory hurdles, pharmaceutical companies focused on developing antibiotics for intravenous use only. Clinical trials for in-hospital use often involved smaller patient populations with more limited usesfor more serious infections. It was believed that parenteral antibiotics would be easier to gain approval, had lower development costs, and could be priced at a premium because many of these infections were life threatening. Also, oral generic alternatives were not competing in the hospital. This resulted in a smaller but positive return on investment.

It is essential that new community antibiotics be developed as methicillin-resistant Staphylococcus aureus is now commonplace and Gram-negative pathogens are increasingly resistant to current agents. [medicograph/]

New Paradigm

Newer antibiotics have an advantage because they were developed to have activity against drug-resistant bacteria. However, activity against resistant bacteria per se cannot be demonstrated showing statistical significance because infections with resistant organisms are rare.

Since statistical superiority cannot be shown due to practical limitations, trial design using noninferiority (NI) margins and guidelines for conducting NI trials were established with tight NI margins of 10%.

The choice of comparator in the trials has also become quite important. The acceptable comparator is not necessarily an older member of the same class of antibiotic being tested, but rather an antibiotic that is the gold standard for the infection being tested.

In this new paradigm, a new antibiotic that is active against resistant bacteria but is somewhat less active in the Phase III  study than the gold-standard antibiotic is not likely to be approved. As a result, a new antibiotic that could be useful to treat resistant bacteria when standard therapy fails may not be available.

Tight measurable endpoints are now required to show that a new antibiotic is NI to the best approved antibiotic. Early 48 to 72 hour endpoints are now selected as the primary end points, while later curative effects have become secondary.

There are two reasons for the selection of early indicators of activity: early endpoints dictate a shorter treatment duration, limiting patient exposure and lowering the probability of resistance selection; and due to the high potency of antibiotics that are now in development, trials using cure rates at the end of treatment do not differentiate them from each other.

However, measuring cures at early time points may be useful when comparing antibiotics within a class, but comparing bactericidal to bacteriostatic antibiotics could lead to misleading results, eliminating more effective antibiotics that have a later but more curative effect. This ultimately limits physician options and negatively impacts patient outcomes. In addition, antibiotics with anti-inflammatory activity may show more rapid clinical improvement but they may not necessarily be better antibiotics.

Antibiotic stewardship is becoming more common than in the past decades, resulting in more conservative antibiotic use as doctors “watch and wait” and limit empiric use to immunocompromised or critically ill patients in teaching hospitals. But in a busy general practitioner or pediatric setting, oral antibiotics are still frequently prescribed. Overuse can be harmful for many reasons including generating resistance, affecting bowel flora, and inducing allergic reactions.

For example, over 35% of pneumococci are resistant to macrolides, and the susceptibility of pneumococci to penicillins has decreased, requiring much higher doses than previously used. In addition, methicillin-resistant Staphylococcus aureus (MRSA) is now commonplace, and Gram-negative pathogens are increasingly resistant to current agents. It is essential that new community antibiotics be developed, but how can these antibiotics be proven safe enough for general use outside the hospital where a larger population is exposed? 

The FDA’s intent is to approve antibiotics only for serious infections (e.g., ABSSSI, PORT 3-4 CABP) within the hospital setting. When proven safe and effective in a postmarketing environment, it may be possible to transition them to outpatient community use. However, it is unclear how an oral-only antibiotic can be approved, as they cannot be used for serious infections that most often require intravenous antibiotics. Oral-only antibiotics will face greater regulatory challenges and require more innovative clinical trial designs. New oral antibiotics may still get approved, but their development will be more challenging than in the past.

Path Forward

Antibiotics treating community-acquired infections can be developed in both intravenous and oral formulations. Having both dosing formulations enables enrollment of moderately to seriously ill patients who require intravenous antibiotics and allows step-down therapy with the oral formulation. In the setting of highly prevalent bacterial resistance for serious infections and the need for urgent empiric therapy prior to culture and sensitivity results, older generic antibiotics can no longer be selected over newer, potent, and more expensive antibiotics.

Unlike other therapeutic classes, for example the statins, it is inappropriate to “try and fail” with older antibiotics. Resistant pathogens can kill the patient. Using the best antibiotic as the first choice in serious infections may be the only choice for that patient. After several years of use, safety can be proven in the setting of broad exposure, Phase IV studies can be conducted, and the oral formulations could become available for out-patient use.

The regulatory and clinical environment has evolved over the last decade with many ramifications. Today, clinical trial guidelines have focused on quantitative, highly measurable primary endpoints that occur early in the course of therapy. New antibiotics must be tested in moderate-to-severe infections, which are usually treated in the hospital. This means that oral-only therapies that are best positioned for treating community infections must take a different approach for seeking regulatory approval.

Pharmaceutical companies that can discover innovative antibiotics, particularly those that can be administered both intravenously and orally, are more likely to succeed through the regulatory process and may have the opportunity to be positioned to treat community infections.

Prabhavathi Fernandes, Ph.D. (prabha@fernandes-domain. com), is president and CEO at Cempra Pharmaceuticals.

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