The COPD Pipeline XVI

Keywords: :

• Drug Approval Process
• placebo
• adaptive trial design
• relovair
• spirometry app.

Clinical Trials and Changes in the Drug Approval Process

Change is coming; it's not just a campaign slogan. I refer to events that affect those of us who have anything to do with clinical trials and the development of drugs and devices. Dr Marianne Mann, former Deputy Director in the Division of Pulmonary and Allergy Drug Products at the FDA and now an independent consultant, has kindly made a short list of apparent trends in the FDA's current expectations. These are:

1. Phase II trials for COPD drugs are critical. FDA wants to understand not only where your drugs work, but where they are suboptimal, so that an optimal dose can be selected for patients.

2. For drugs that work systemically in COPD (orally or parenterally administered products) establishment of their pharmacokinetic profile can help to identify an appropriate dosing regimen (q.d. or b.i.d, etc). Nonetheless, the dose and regimen for clinical efficacy and safety must still be determined in Phase II, and a range of doses and regimens are often explored in these studies.

3. A key goal of any COPD (or asthma) program is to replicate the efficacy findings at the lowest optimal dose. Before going to phase III with a combination product, FDA may require replicate phase IIb trials of 12 weeks duration of one or both components.

4. Pending determination of the lowest optimal dose and regimen in phase II, pivotal phase III trials often still explore 2 doses of active drug versus placebo. Thus, dose finding often continues into phase 3 trials.

5. For inhaled drugs, the pharmacokinetic profile cannot determine the dosing interval. Pharmacodynamic data are needed to provide support that a drug works once daily or twice daily, etc. For drugs such as bronchodilators, FEV1 data are needed to support the dose and regimen. For these drugs:

   1. Initial phase II trials should include a wide range of doses. One should attempt to include a “no effect” or clearly suboptimal dose as well as peak drug effect dose, and well distributed doses between these. Placebo is always included in such trials.

   2. In phase IIb, it is advisable to give attention to when pharmacodynamic steady state is reached. This applies to bronchodilators as well as non-bronchodilators. Thus phase II trials should capture the time to steady state efficacy. Crossover studies usually involve single doses, and although this is acceptable to design more definitive dose-studies, the phase IIb trial will usually need to employ a parallel-arm, longer duration format.

   3. A two to 4 week trial typically captures pharmacodynamics steady state for most known bronchodilators, but each new product must determine this for itself. FDA often recommends trials of at least 2, if not 4 weeks in duration for key phase IIb bronchodilator trials accordingly.

   4. Once an optimal dose range is narrowed, exploration of the regimen may also be required. FDA's strictest challenge is an internal comparison of q.d. regimens of drug versus b.i.d. (split dose) regimens. Sometimes the use of an already approved drug (given q.d. or b.i.d. according to its label) can also provide support that the regimen being proposed for the new drug is reasonable. Double-blinding of the approved agent in such trials can be a challenge, however.

   5. As noted above, the gold standard support for a regimen comes from comparisons of a novel bronchodilator given q.d. versus b.i.d., and FDA may require such studies, particularly for a q.d drug. While the same total nominal dose, e.g. given q.d. versus b.i.d., is of interest, there is also interest to compare dose 1X q.d. versus dose 0.25X b.i.d. Should this latter comparison look equivalent pharmacodynamically, the lower dose b.i.d. regimen may be preferred.

   6. Once dose and regimen and the pharmacokinetic profile of the bronchodilator are well understood, an end-of-phase II meeting with FDA will help clarify future phase III plans.

   7. To obtain an indication for COPD for a LABA, FDA has recently advised phase II work to be done in asthmatic subjects or bronchodilator responsive COPD patients. Typically, for LAMA products, reactive COPD subjects are acceptable. While the phase II trials are therefore “enriched” to show dose response, this is the objective of the trials and is acceptable. Phase III trials should not be thus enriched and should include COPD patients without regard to their airways reactivity.

   8. COPD phase III trials typically include a minimum of 3 treatment arms: placebo, and two selected doses (or regimens) of the experimental agent. They must last a minimum of 12 weeks in duration. Trough FEV1 is a typical primary efficacy endpoint, or is one of 2 co-primary endpoints.

   9. Safety databases must consider particularly longer term safety data, typically out to one year. A comparator arm such as an approved agent, even if it cannot be blinded, is highly advisable. Given the serious nature of COPD, serious adverse events will occur in long-term studies and the presence of a comparator arm can help interpret subtle findings that may raise concern for a new chemical entity.

   10. While trough FEV1 values are often selected as a primary efficacy endpoint in phase II dose-finding trials for bronchodilators, the entire FEV1 curve over the dosing interval should be fully characterized in either the entire group of randomized patients or a significant subset. FDA does not focus solely on trough FEV1 data and will evaluate all spirometry data to determine the optimal dose and regimen.

The Unobtainable Placebo

The metered dose inhaler, once the universal delivery device for inhaled agents, is losing ground. In its place we find a stream of delivery devices, all of them unique in design and all proprietary products. One consequence, whether intended or not one cannot say, is that without a matching placebo an independent investigator cannot readily conduct a double-blind study of the product that is delivered by that unique device. Nor can one compare the drug's performance with an alternative product.

Pharmaceutical companies almost never make their delivery devices, whether placebo or active, available to independent investigators. In one reported instance, the company required the investigators to submit their research protocol, which, when it was submitted, they would only provide a placebo device if the protocol was changed according to the company's suggestions (1). Other examples mentioned by the authors disclose tactics such as charging an ‘extraordinary amount of money’ for a placebo or outright refusal.

In effect, companies can control or prevent any independently planned and conducted head-to-head study of their product if it requires the use of a unique and proprietary delivery device or formulation. This requirement, of-course, applies to almost all our COPD drugs.

In defense of companies it must be stated that there is no legal requirement for a company to make its assets available to outside agents. Development of any medical therapy is extraordinarily expensive and companies own the intellectual property they develop and patent. They are under no legal obligation to provide it to others. One can criticize such withholding as thwarting unbiased evaluation of their product and placing their credibility in doubt. Some authors consider withholding a placebo from wider access unethical (1). But lawyers could argue on either side of the issue.

This situation limits our ability to perform independent assessment of many of the products we use in COPD, but not, interestingly, those that are delivered by nebulization.

Adaptive Trial Design

The traditional clinical trial requires that the protocol, in every detail, be set in stone before the trial begins and any change during the course of the trial is a deviation or violation. However, it may become clear during the trial, from adverse events or interim analysis, that the trial design was suboptimal in some way. The traditional response requires that another trail with an improved protocol must be performed. This results in delay and expense. An approach that could avoid such problems is the adaptive design trial, about which I briefly reported in a previous Pipeline (2). This allows predetermined changes of protocol to be instituted during the course of a trial. The crucial aspect of adaptation is that all eventualities that may warrant a change in the protocol must be prespecified before the trial begins. But almost any changes one can anticipate needing can be included, -dosages, regimens, discontinuing ineffective dosage arms, increasing or decreasing enrollments, etc. Statistical integrity is maintained because and only if the change was prespecified in the protocol. The FDA has now provided Guidance (3). Adaptive trials are becoming more widely used but it is not yet clear whether the additional complication of covering all potential eventualities pays off. Using the search term “adaptive design”, clinicaltrials.gov currently lists 77 trials, 2 of which are for COPD agents.

Relovair is the once-daily ICS-LABA combination in late-stage development by GlaxoSmithKline and Theravance. The components are fluticasone furoate and vilanterol. Aimed to replace the GSK product, Advair, which will lose patent protection this year, Relovair will be submitted for regulatory approval in mid-2012, according to reports. Its once-daily dosing will no doubt be put forward as a desirable compliance-enhancing feature. Pivotal trials show that the agent is effective both in improving lung function and reducing acute exacerbations of COPD. However, in a 1,600 subject head-to-head trial against Advair, Relovair did not show superiority. There were also concerns that fatal pneumonia has occurred in some of the studies. Some reports predict problems with FDA approval in USA.

A novel study of Relovair in both COPD and asthma subjects was due to begin in March this year, -the Salford Lung Study. This will be a large, prospective, ‘real-world’ study in a single community in UK. The novel feature is that “the initiative will draw on Salford's e-Health records infrastructure, ..a single, integrated electronic patient record across primary and secondary care. Patients are closely monitored ..yet with minimal intrusion into their everyday lives.”

A Spirometry App? Ophthalmologists see a need for eye exams in remote areas where there is no optometrist to do eye exams and prescribe corrective lenses. Their solution, already developed at MIT's Media Lab and available for $2, is an app that can do an eye exam anywhere a modern cell phone will work. If you don't believe me, see http://itunes.apple.com/us/app/vision-test/id380288414?mt=8or http://www1.whdh.com/news/articles/local/boston/12002340870113/new-eye-exam-app-made-by-mit-available-soon/. So why not a spirometry app? Same problem. Go to it MIT.