Singular Approaches to Combination Trials

The advent of new drugs for tuberculosis is posing some interesting challenges for regulators in Europe.
Apr 01, 2014

In early March, the European Commission granted conditional approval to Janssen Therapeutics' Sirturo (bedaquiline), for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients. Another new drug, Deltyba (delamanid), developed by the Japanese company Otsuka Pharmaceutical Co., has also been recommended for conditional approval by the European Medicines Agency (EMA).

The recommendations are for only conditional approvals, since the products have completed testing only up to Phase IIb of clinical trials. In addition, the opinion specifies only second-line use, as part of combination therapy. Sirturo can be used only when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability, according to Janssen. Wim Parys, the company's head of R&D and global public health, said Janssen will now "continue to work with partners and relevant authorities to ensure Sirturo is used correctly and appropriately."

This will be no mean feat. As the company says, "Under the provisions of the conditional approval, Janssen commits to support a Phase III study to further substantiate the benefit-risk for Sirturo and to define its optimal use, with regards to the number and types of agents that are needed in combination, and its optimal treatment duration."

No clear evaluation path

The challenge now—for Sirturo, and in due course for Deltyba—is to see how they can be constructively inserted into the combinations currently used to treat TB in a way that will shorten treatment duration or ease the side effects. In Europe, that is still far from obvious. There is a guideline from the EMA on clinical development of fixed combination medicinal products, issued in February 2009 by the Committee for Medicinal Products for Human Use (CHMP). But working out new treatment regimens for TB with new products is rather more complex than using fixed combinations.

Last February, CHMP indicated that the guideline was under revision. The committee issued a concept paper on the need to revise the guideline, for a number of reasons, including updating it "to minimize reference to regulatory aspects (e.g., dossier requirements)," and to "update the scientific aspects of the guideline." That revision is still underway, and EMA sources say it is likely to take most of this year to reach any conclusion. Meanwhile, the attempts to identify the most appropriate regimens for the new TB medicines will have to move ahead in something of a void.

US moving faster

The FDA has taken a more rapid path to this dilemma. In June 2013, the agency issued a guideline of its own. Noting that combination therapy "is an important treatment modality in many disease settings, including cancer, cardiovascular disease, and infectious diseases," FDA noted how "recent scientific advances have increased our understanding of the pathophysiological processes that underlie these and other complex diseases," and have in turn "provided further impetus to develop new therapeutic approaches using combinations of drugs directed at multiple therapeutic targets." The rationale can be to improve treatment response, minimize development of resistance, or minimize adverse events.

In settings in which combination therapy provides significant therapeutic advantages, the FDA document states, "There is growing interest in the development of combinations of new investigational drugs." And because "existing developmental and regulatory pathways focus primarily on assessment of the safety and effectiveness of a single new investigational drug acting alone, or in combination with a previously approved drug," FDA believes guidance is needed to assist sponsors in the codevelopment of two or more new investigational drugs.

The FDA guidance is intended to describe a high-level, generally applicable approach to codevelopment of two or more new investigational drugs. It describes the criteria for determining when codevelopment is an appropriate option, makes recommendations about nonclinical and clinical development strategies, and addresses certain regulatory process issues. The guidance doesn't answer all the questions, but it is a start.

European needs

It's not just one drug for TB that's needed. You need multiple compounds that work as cocktails that don't interact or have multiple adverse reactions," Dr. Evan Lee, VP of Eli Lilly's Global Health Programs and Access, told this columnist recently. "Collaboration helps in terms of generating that cocktail."

Professor Frank Cobelens of the University of Amsterdam takes a similar view. He commented recently that companies may balk at the cost of extensive trials under current arrangements. The two new medicines will need to be field-tested in clinical trials that evaluate the efficacy and safety of drug regimens (e.g., combinations) rather than of individual drugs, and while industry is willing to invest in Phase III trials needed for licensing, drug companies for understandable reasons are reluctant to make the huge investments needed in such combination trials.

"One major technical limitation is the lack of valid markers to predict treatment outcome," says Cobelens. "So that trials need to follow up patients for the entire duration of treatment plus another 12 months or so to see if patients relapse, making trial duration for a single patient at least 18 months for drug susceptible TB, and at least 36 months for MDR-TB."

In addition, because new drug regimens need to be compared to current standard, requiring large numbers of patients to be evaluated across many sites, trials are expensive. This has been feasible for drug susceptible TB, but "it is a major challenge to do this for MDR-TB." In his view, "concerted efforts are needed to bring together trial capacity and funding in order to find out the drug combinations that are best used against MDR-TB."

Easing access to new therapies

One approach pioneered—at present only as a theory—by campaigning group Médecins Sans Frontières (MSF) is to multiply the search for effective combinations by allowing wider access to candidate therapies. The group has recently sought—unsuccessfully— World Health Organization backing for a project that would test the theory.

"TB must always be treated with a combination of drugs, but a lack of collaboration and transparency means that clinical trials to test these new drugs in the combinations needed will not be completed until years after these drugs are registered," says MSF in explaining its plan. "Many organizations working in the area of regimen development, including TB Alliance, UK's Medical Research Council (MRC), and RESIST-TB, have encountered obstacles caused by today's R&D framework, for example, in accessing new drug compounds for testing new treatment regimens."

MSF proposes the sharing of data, the pooling of intellectual property and "the creation of incentives for multiple actors to enter the R&D process in order to accelerate development timelines" by leveraging "as much existing capacity and expertise in TB as possible to foster greater collaboration between researchers."

MSF's Helle Aagaard says the current regulatory and economic system "results in drugs being brought to market individually, even though what we need for TB is new drug combinations and regimens." In her view, "The research collaboration required to bring new regimens to market will not take place without government-led policies and incentives in place to encourage it."

The scientific approach

Europe is also trying to solve the problem through a more scientific approach. The Innovative Medicines Initiative (IMI), a project funded by the European public-private partnership focused on early-stage research, is aiming to speed up the search for new, more effective combinations of treatments to tackle TB. "Current clinical trial methodologies make it very difficult to evaluate the optimal doses and combinations of drugs," says IMI. "Putting together a new, shorter treatment regimen could take a quarter of a century using today's methods." IMI, therefore, is running a project known as PreDiCT-TB, focused on tackling preclinical research barriers to the discovery and development of new TB drug combinations. It is exploring methods that can be more effective than the current trial-and-error method in which new drug candidates are developed and added to the existing regimen one by one.

PreDicCT-TB is developing an integrated set of laboratory-based models that will provide data to indicate the most appropriate doses and combinations of drugs for patients. In addition, the project will generate a database of patient data from previous and on-going clinical trials, as a reference for evaluating the performance of combination anti-TB drug regimens in these newly developed laboratory models. Ultimately, the aim is that researchers will use the information generated by the novel models to design better clinical trials involving TB patients.

However Europe goes about it, the need is clear for maximum speed as well as maximum efficiency. The latest data from the European Centre for Disease Control (ECDC) shows that multi-drug resistance poses a serious challenge in the attempt to eliminate TB across Europe.

"The target of a declining five-year trend for MDR-TB was achieved by only seven of 21 reporting countries," says ECDC director Marc Sprenger. "Overall, Europe does not have a good track record."

Only one in every three patients in the EU finishes MDR-TB treatment successfully. More than half either die, fail treatment, or default from treatment. That should be a spur to action.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.