Toward Clinical Transparency
I have reported previously on concerns about the relationship between industry and physicians when it comes to reporting the results of clinical trials (Citation1). Usually, a pharmaceutical company designs its own trials, perhaps with input from a few outside consultants, and administers every aspect of the trial, which includes paying for it. Traditionally, the company analyses the data obtained from the trial. All of those data, every page of them, must be submitted to the FDA, who holds the data in strict confidence. The tricky part comes when and if the results are to be published. Usually, industry retains full control over what is reported, including what data it provides to the investigators whom they commonly invite to write and publish the reports—us. Or, industry may decide to hold all the results and not to publish at all. (Part of the purpose of the clinicaltrials.gov website was to inform the public what studies were being performed and then to publish them.)
Unfortunately, the number of completed studies that achieve publication is quite small. As of time of writing, the search term “COPD or Emphysema or Chronic bronchitis” yields 1,053 completed studies and only 104 of them, 10%, claim to have results. Moreover many of these “results” cannot be found or refer only to a package insert). But if the results are published there is nothing, at present, to prevent industry from publishing only those data that support their product. Selective reporting of trial results can and sometimes has led to distortion or misrepresentation of a product's qualities. An example was when a well-known company made claims about the efficacy of its asthma product based on a study whose claims the FDA had rejected. The company denied wrongdoing but agreed to a sizeable “fine” (Citation2).
Big Pharma is now making initiatives to be more transparent. Last October GSK announced it plans to “allow researchers to examine the data more closely….to help optimize the use of medicines with the aim of improving patient care.” A website will be created containing detailed patient data and the full protocols of clinical trials that GSK has conducted for approved and discontinued drugs. Importantly, the site would contain results of failed, as well as successful, trials. However, access will be limited to ensure that, the company says, “this information is not misused, which could be detrimental to medical science and patient care. Research requests will need to be submitted with proposals, which will be reviewed for scientific merit by an independent panel of experts.” If this does not sound exactly as transparent as one had expected, one must bear in mind that the data belong, in the first place, to the agency that generated them.
Only then can the rest of the world, researchers and research subjects claim the right or privilege to see them. Must a company reveal its findings to a competitor? Are there concerns that data could be misrepresented by non-experts? Or by anyone with a grievance against the company? We await with interest the establishment of this site and, one hopes, the sites of other pharmaceutical companies.
Pipelines under Pressure
With about 130 pharmaceutical products, 14 of them blockbusters, going off patent in the next 3 years, and not many obvious potential blockbusters coming on-line, big Pharma is taking measures to maintain their profitability and competitiveness. One part of the strategy is to downsize; another is organizational restructuring. That much one can understand. Other measures include closer collaboration with each other (really?) and with academic institutions (a very good idea) and outsourcing discovery to contract research organizations (Hmm..!). Other defensive strategies are described in industry reviews. http://www.dddmag.com/articles/2012/05/pipelines-under-pressure-take-new-paths?etcid = 2903582&etrid = 227339699&linkid = http%3a%2f%2f www.dddmag.com%2farticles%2f2012%2f05%2fpipelines-under-pressure-take-new-paths. It's hard to know how these changes in the amount and range of drug development will affect us as clinicians.
One concern is that when Pharma looks at where the most profitability with the least risk can be found, they see 2 types of drugs. One is in what one might call “blockbuster territory”—the common, chronic diseases, particularly if a treatment that lends itself to a “me-too” knock-off has already been approved. The second place is for an orphan disease. Consider these two strategies. As pulmonologists we are familiar with the first strategy, with Advair being the class originator, followed by Symbicort in 2011, and several LABA/ICS products in development looking to take a piece of that pie.
The differences between these products are limited to once-daily or twice daily, the delivery device, dry powder MDI or nebulized, and such issues. The differences are rarely groundbreaking, but there is value in having alternatives. However, most of the strategic drift in drug development is going towards oncology, neurodegenerative diseases, cardiology and diabetes and, I fear, away from pulmonary. Possibly this is because the basic science to support research into new drug classes for COPD is not there and partly because the path to FDA approval for COPD drugs can be difficult. We lack realistic and acceptable endpoints; perhaps the ongoing endeavor to validate biomarkers in COPD will address our lack of endpoints. The fact remains that there is a disproportion between the size of the COPD problem and Industry's interest in addressing it.
Orphan Drugs
Orphan drugs and diseases represent Industry's alternative strategy to maintaining profitability. There are between 5,000 and 7,000 such disorders, and by U.S. definition, they are disorders that afflict fewer than 200,000 individuals or about 1 in 1,500 of the population—not such a small number. (In Europe and elsewhere “rare” is defined as 1 in 200,000.)
The attraction of orphan diseases for a pharmaceutical company is largely due to the Orphan Drug Act of 1983 and the Rare Disease Act of 2002, which aimed to encourage the development of treatments for rare diseases by offering financial incentives. In the United States, the sponsor is qualified for reduced taxes and to sell without competition for 7 years, among other benefits. The FDA works cooperatively with the developer to facilitate the approval process, resulting in a shorter time to approval. Also, competition is very unlikely. The profits accrue from the enormous costs that orphan drugs can command, e.g. $375,000 per patient per year for Elaprase for Hunter's syndrome.
About 460 drugs for designated rare diseases are now under development—an increase of more than 200% since 2011. Novartis, GSK and Pfizer now each have units for research into designated rare diseases, and NIH has a grant program specifically for similar purposes. Fully one third of new molecular entities approved by FDA last year were orphans, http://www.rsc.org/chemistryworld/2012/09/ orphan-drug-economically-attractive-growth. The market for orphans has grown faster than that for non-orphans. (Industry types have a saying: “the orphans are growing up”). The global market for orphan drugs was worth $50 Billion at the end of 2011. Compare that with the market for all COPD drugs at $5.5 Billion. Almost half the orphan drugs in development are for cancers and cancer-related conditions. Genetic disorders garner 66 or 14% of the 460 rare disease drugs and respiratory has only 15 or about 3%. These include alpha-1 antitrypsin deficiency, cystic fibrosis, and the pediatric condition, congenital lobar emphysema. The FDA granted rare drug designation to sirolimus for the treatment of LAM last year. But oral remodulin, the other pulmonary orphan drug submitted for a PAH indication last year, was denied approval.
Cyclosporine-A for COPD
The website Clinicaltrials.gov lists 10 studies, 5 of which are ongoing. One additional trial has just begun and is not yet listed in that website. Cyclosporine A (CsA) reduces the activity and growth of T cells and is used to suppress rejection due to transplantation of many organs. However, when given systemically, the usual route, it has serious liver and renal toxicity as well as other drawbacks. For this reason, 8 of the 11 ongoing studies employ inhaled formulations of CsA, either as nebulized suspensions, in liposomal form (designated L-CsA), or as a dry powder. The comparison is with oral cyclosporine. In each study the drug is initiated at the time of transplantation and continued as maintenance therapy. The endpoint is usually classified as “safety/efficacy” and the usual primary outcome is stated as frequency of rejection or time to the first rejection event, e.g. bronchiolitis obliterans. In 3 trials the primary outcome is lung function.
In the ongoing NIH study of stem cell transplantation for COPD (NCT01287078), CsA is initiated at the onset of post-transplant rejection. Only one study (NCT01429844) compares CsA with another active drug, in this case tacrolimus. The trials range in size from 7 to 75 subjects for Phase I to II trials, up to 284 subjects for a Phase III trial.
Two other trials of CsA are in severe COPD but not following transplantation. Both are small Phase I trials, with safety as the endpoint and trial durations of 4 and 16 weeks (NCT00783107, 00974142). These studies test the potential role of CsA to address the ongoing inflammation in the airways in COPD, a concept for whose support there is a publication (Citation3).
Of non-pulmonary interest is that CsA crosses the blood–brain barrier and is reported to have strong neuroprotective properties. The molecular mechanism of CsA is that it blocks the formation of the mitochondrial permeability transition pore, and much of the damage associated with head injury is thought to be due to that pore. Thus, there are ongoing trials in Europe of CsA for traumatic brain injury (TBI). None of these trials are listed in clinicaltrials.gov.
Rosiglitazone
The drug approved as Avandia for diabetes is being studied in COPD for its potential anti-inflammatory action as a PPaR-γ antagonist (NTC 01174056). In a parallel arm single-blind controlled format, healthy subjects will receive endotoxin following 2-week treatments with either rosiglitazone or zileuton. FDG-PET and BAL will be employed to detect a decrease in the inflammatory response.
MEDI-7814
This is an AstraZeneca/MedImmune drug that has recently completed Phase I. According to its entry in clinicaltrials.gov it is “a human immunoglobulin G4 (IgG4), effector-null, neutralizing monoclonal antibody (MAb) that is specific for human complement components C5, C5a, and C5a desArg, and prevents the binding of C5a to its receptors C5aR and C5L2.” The primary outcome was safety.
N-Acetyl Cysteine (NAC)
This is an agent that has a long history for its claimed ability to liquefy mucus, as an anti-oxidant, and as a treatment for acetaminophen toxicity. Its efficacy by inhalation as a mucolytic is no longer generally accepted, but it continues to be studied as an oral agent for its potential anti-inflammatory and/or mucolytic actions in respiratory conditions where mucus production and a bronchitic component are predominant features.
There are currently 3 completed trials in clinicaltrials.gov, 3 identical trials at an early stage, and 1 trial with unknown status. All enroll subjects with predominantly bronchitic COPD. The duration of the trial varies from a few weeks to 12 weeks (one for 3 years) and use dosages from 600 mg once daily to 1,800 mg twice daily. The primary outcome in the 3 identical studies is the SGRQ; exacerbation frequency in 2 others and improvement in air-trapping as measured by an increase in IC. No publications related to these trials are cited.
Acknowledgments
Some of the information presented in this column was made available through Citeline's Trial Trove©. For more information on Trial Trove, please visit www.citeline.com
References
- Gross NJ. The COPD Pipeline XVII. COPD 2012; 9:432–434.
- Editorial: Toward clinical transparency. Nat Med 2012; 18:1593 doi:10.1038/nm.3000.
- Onoue S, Inhalable dry-emulsion formulation of cyclosporine A with improved anti-inflammatory effects in experimental asthma/COPD-model rats. Eur J Pharm Biopharm 2012; 80:54–60.
- McCormack FX, Efficacy and safety of sirolimus in lymphangioleio- myomatosis. N Engl J Med 2011; 364:1595–1606.