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Abstract
Registrational trials in rare and orphan diseases present complexities related to the identification of subjects, recruitment, logistical hurdles incumbent with far-flung study sites, and end points that are often less well defined than are those used in more common illnesses. Alpha-1 antitrypsin deficiency is an orphan disease of genetic origin that carries the additional challenges of variable penetration and slow disease progression. Registrational trials of augmentation therapy using plasma-derived alpha-1 antitrypsin carry all of the above-noted burdens, as well as competition from commercially available augmentation therapy in many countries.
Alpha-1 Antitrypsin deficiency (AATD) was discovered in association with pulmonary emphysema in 1963 by Laurell and Eriksson (1). Augmentation with human donor plasma-derived alpha-1 antitrypsin (AAT) was approved to treat deficient patients in the United States in 1987. However, this approval was not based on evidence of efficacy in clinically relevant outcomes such as progression of pulmonary emphysema. Rather, recognizing the difficulty of identifying sufficient subjects to support a traditionally powered clinical trial, augmentation was approved on the basis of biochemical efficacy, defined as (2):
| 1. | Evidence that intravenous augmentation therapy raises serum levels above the target protective threshold and does so over the entire interdose interval | ||||
| 2. | Evidence that the functional capacity of infused pooled human plasma AAT to oppose neutrophil elastase is preserved after the drug is infused. | ||||
Evidence of delayed progression of emphysema, or progression to death, has been slow in coming and arguably has yet to arrive when viewed through the strict lens of standards of proof of efficacy applied in registrational trials (3).
With four U.S. Food and Drug Administration–approved AAT augmentation products available in the United States that are supported by four sponsors, why has industry struggled to deliver inarguable evidence of clinical efficacy for at least one?
Support of research and development (R&D) activities of a single agent, or class of agent, never exists in a vacuum. Broad industry and economic trends affect the ability of a company to pursue all desired R&D activities. Furthermore, the regulatory environment is largely shaped through the review needs and the approaches used to assess small molecules and more common biologic agents such as monoclonal antibodies. It is worthwhile to step back from augmentation therapy to assess the influence of broad industry issues over the decades since the approval of augmentation therapy. It is also useful to review the impact of laws designed to spur the development of treatments of orphan diseases.
Success rates in the development process of new pharmaceutical agents affect sponsors’ financial ability to incur the risk of a logistically daunting trial, such as would be needed to demonstrate conclusively the efficacy of augmentation therapy. Attrition of candidate agents occurs at each stage of preclinical and clinical trials program (Figure 1) (4). This resulted in a rate of regulatory approval of approximately 5% for those candidates who survived the preclinical stage to enter into human trials in the period of 2006–2008. Remarkably, this figure reflected a drop in the success rate from the 10% rate reported in 2002–2004.
Figure 1. Probability of success to approval from key milestones. Candidate pharmacotherapies endure a significant attrition rate at all steps before approval. Within the decade of the 2000s, there was a fall in overall success from entry into human trials to approval from 10 to 5%. Adapted by permission from Reference 4.
[More] [Minimize]Recalling that augmentation therapy was approved in 1987, what was the development environment like during the following years? The 1980s and 1990s are often seen as a particularly productive time in new drug development. However analysis of trends in R&D costs and the number of new chemical entities (NCEs) developed reveals an upward inflection in R&D spending, outpacing the upward trend in the number of NCEs resulting as far back as the mid-1980s (Figure 2) (5). This imbalance resulted in a rapid rise in expenditures per NCE. Whereas research inflation rates per new drug in the 1970s were 6.1% and 7.3% (out of pocket and capitalized, respectively), these rates rose to 11.8% and 12.2% by the decade of the 1980s (5).
Figure 2. Inflation-adjusted industry research and development (R&D) expenditures (2000 dollars) and new chemical entity (NCE) approvals in the United States from 1963 to 2000. From the 1960s through the year 2000, industry R&D activities experienced a significant rise in expenditures vs. approved NCEs. Reprinted by permission from Reference 5.
[More] [Minimize]Industry responded with several approaches that were hoped to improve R&D productivity, perhaps most prominently high-throughput screening, a highly automated means of testing large numbers of molecules against a selected target. Unfortunately, success remained elusive, and R&D expenditures did not moderate until 2008, with new agent approvals reversing a strong numerical decline at about the same time (6). Before this reversal, the R&D environment was not conducive to accepting additional risk for an approved agent treating a very small population, such as AATD. However, by 2010 the environment was improving.
Additional improvement in the environment occurred in the form of orphan disease legislation in the European Union in 2000 and in the United States in 1983 and 2002. In the United States, an orphan disease is defined as one affecting fewer than 200,000 people. The Orphan Drug Act of 1983 reduced the statistical burden necessary to achieve approval of a drug serving an orphan disease, allowed tax benefits of up to 50% of development costs and provided additional clinical research subsidies. Market exclusivity above that enjoyed through a conventional drug patent was also provided. The 1983 act provided a 7-year period of market exclusivity that differs in that it does not begin until the drug is granted marketing approval. Furthermore, during this period, a subsequent competing candidate for the same indication must demonstrate superiority to the leader to gain market entry.
The US Rare Disease Act of 2002 built upon the Orphan Drug Act of 1983 by funding the Office of Rare Diseases under the National Institutes of Health; this office serves a critical coordinating role in rare disease research. European Union rare disease policy has the additional benefit of specifically encouraging member nations to take steps to identify individuals with rare disorders and to maintain registries.
The impact of this legislation has been dramatic. Ten new agents for orphan diseases were approved between 1973 and 1983. More than 400 have been approved in the years since 1983 and 31 such agents were approved in the year 2013 alone. But medical need and commercial opportunity for additional R&D in this area persists; it is estimated that 95% of rare diseases do not have a specific treatment (7). Industry has turned its attention to meeting this need, reflected in a steady rise in the percentage of total branded drug sales represented by orphan disease treatments, rising to 10% in 2011 and projected to rise to above 20% by 2020 (7). The economic and regulatory environment for orphan disease R&D has become more favorable.
The challenges specific to testing augmentation in a well-controlled trial can be placed into three broad categories: subject population, end point selection, and logistics.
The number of individuals affected by AATD in the United States is small, estimated to be 100,000 people; this number is further complicated by the estimate that only 10% have been identified (8), substantially limiting the population available for trials. For those individuals identified, a further barrier is presented by the availability of augmentation therapy in large countries such as the United States, Germany, and Spain. An individual agreeing to participate in a multiyear placebo-controlled trial is accepting the risk of being randomly assigned to the placebo arm. In addition, should the individual choose to participate, maintaining subject blinding can be problematic given the availability of testing AAT blood levels through commercial laboratories. Indeed, the dropout rate in the placebo arm of the RAPID trial was twice that of the active treatment arm, a difference that achieved statistical significance (9). Finally, as also suggested by the open-label extension portion of the RAPID trial, it appears that tissue lost while on placebo is not regained after delayed initiation of augmentation (10), creating an important health risk for the subject and an ethical challenge for the participating investigators and the sponsor.
The traditional measure of progression of emphysema has been FEV1, used in the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin (11). This measure enjoys the benefits of being low cost, low risk, and widely available. Unfortunately, it is a relatively insensitive and variable measure of progression (12). Using the observed FEV1 results of the NHLBI Registry (21 ml per year difference), an estimated 213 subjects per arm, followed for 4 years, would be required to adequately power a placebo-controlled trial of augmentation on the basis of rate of FEV1 decline (13). Despite these clear limitations, FEV1 continues to enjoy great acceptance as an end point within the pulmonary community, perhaps related to a history of use going back to the mid-20th century (14).
Lung densitometry measured by computed chest tomography has been developed over the past 15 years as an alternative to FEV1 (15, 16) and is gaining acceptance within industry and the regulatory community. An augmentation therapy has received marketing approval from the European Medicines Agency (EMA) on the basis of a pivotal trial using lung densitometry as its primary end point (17). Another manufacturer is also seeking EMA approval, as well as completion of a postmarketing commitment to the U.S. Food and Drug Administration, via a trial using densitometry (18).
Lung densitometry is more sensitive than FEV1, provides a wider array of information, and correlates with mortality (19). Unfortunately, it exposes subjects to radiation, there is variation among and within scanners, and it is expensive relative to pulmonary function testing. Perhaps most concerning from the standpoint of conducting a clinical trial, it lacks the long history of use enjoyed by FEV1. Analysis of the derived raw data is still evolving.
The potential pitfalls provided by this evolving understanding are revealed by a brief review of three of the factors that the investigator must address in obtaining and analyzing the data. First, the investigator must select a methodology of correcting for the degree of lung inflation between two or more scans (statistical correction vs. physiological correction); he/she must also decide whether to adjudicate the density change over time on the basis of a comparison of two time points (end point analysis) vs. slope analysis. These decisions were explored in the EXACTLE trial yielding four potential combinations of correction method vs. adjudication of change (20, 21). The most favorable combination was statistical correction and end point analysis. But it is important to note that the range of P values for the four combinations fell over a narrow range, from 0.049 to 0.084. These values are based on only 67 subjects who completed the trial.
Perhaps an even more basic decision is the selection of a point or points in the ventilatory cycle to measure lung density. The selection should be reproducible between computed tomography (CT) scans to reduce noise, while permitting a compromised patient to perform a breath-hold of sufficient duration to obtain the scan without movement. The recently completed RAPID trial used the average of densities obtained at two points in the cycle: FRC and TLC. The ongoing SPARTA trial uses only measurement at TLC for the primary end point (18).
The RAPID trial’s selection of the average of the densities at FRC and TLC as the primary end point yielded a P value just above statistical significance at the conclusion of a trial that took 6–7 years to execute (9). The secondary end point of density at TLC would have provided statistical success had it been the primary end point, indicating the implications of our relatively short experience with CT densitometry. The decision to use the average of FRC and TLC was entirely reasonable on the basis of the information available at the time it was selected. This also focuses attention sharply on the risk incurred by adopting a fairly new end point that the industry R&D “first mover” accepts.
Although CT densitometry and FEV1 remain the preferred end points in augmentation trials, a recent trial for European Union registration used the respiratory exacerbation rate in the subset of deficient patients with frequent exacerbations. Hyperpolarized magnetic resonance imaging holds promise as a means of measuring emphysema progression without irradiation, but is early in its development.
AATD subjects can be identified wherever individuals of European heritage have settled. This means that trials that seek to recruit in a reasonable period of time must be prepared to recruit from Europe, North and South America, western Asia, and Australia and New Zealand. The diversity of countries carries with it substantial differences in local regulations, ethics review process, subject safety, and issues as mundane as using a common spirometer model across all sites when there may be none approved in all participating countries. Of course, the broad range of time zones involved also complicates coordination of sites and adds to the expense.
A second consideration of note is the availability of multiple augmentation clinical trials and approved products. Both competing trials and approved therapies provide alternatives for potential subjects, reducing available subjects for the sponsor’s registration trial. A related form of competition that cannot be overlooked by the sponsor is the potential for competing manufacturers who elect to delay a clinical efficacy trial to benefit from the evidence derived from the successful outcome of the first mover’s trial. This is a particular issue in countries with multiple approved augmentation products, especially should regulators and payers wish to foster a competitive environment to reduce augmentation prices.
The ability to conduct a traditional clinical efficacy registrational trial of AAT augmentation therapy remains challenging, although less so than in 1987 when it was first approved on the basis of biochemical efficacy. Conducting such a trial has been aided by an increased population of identified deficient individuals, an improved end point, and a more favorable financial environment for pharmaceutical development, in addition to improved regulations and incentives specific to orphan and rare diseases. Despite these recent changes, substantial logistical challenges remain. And some difficulties are worsening, particularly in regard to the ability to recruit subjects for a placebo-controlled trial when augmentation is increasingly available on the commercial market. It remains to be seen if the SPARTA trial can overcome these barriers to achieve its primary end point.
There are a number of potential approaches for increasing the likelihood of logistical success of a traditional registrational trial of augmentation:
| 1. | Improved subject identification through low-cost birth screening and/or family screening | ||||
| 2. | Enhanced patient risk stratification within deficient individuals (i.e., rapid decliners) to focus on individuals with the greatest need and greatest ability to demonstrate benefit | ||||
| 3. | Nonmonetary compensation of participants for the risk incurred through possible random assignment to placebo | ||||
| 4. | Improvements in CT technology, including reconstruction and analysis software, and reduction in radiation exposure | ||||
| 5. | Validation of new, more sensitive outcome parameters with strong clinical correlates (e.g., magnetic resonance imaging, gas exchange surface area) | ||||
| 6. | Careful extrapolation between nondeficient and deficient emphysema learnings regarding end points | ||||
| 7. | Creation of legal space for drug companies to work collaboratively on AATD trials, and/or creation of financial incentives for the company leading the way to the benefit of multiple manufacturers | ||||
| 8. | Harmonization of international regulation around conduct of clinical research | ||||
The broad α1 community of patients, providers, and manufacturers best understands the need and the attendant issues involved in research in this disorder and must advocate for required changes.
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The views expressed are solely those of the author and are not intended to reflect those of GlaxoSmithKline.
Author disclosures are available with the text of this article at www.atsjournals.org.
