Do Expedited Drug Development Programs Do More Harm Than Good?
Written By Fiona Chisholm, Analyst for GBI Research
The pharma industry is renowned for its time and cost-intensive R&D practices. In the US, it typically takes at least 10 years to bring a new drug to market, at an estimated cost of $2.6 billion, which includes the cost of many potential drugs that did not reach the market (PhRMA, 2015). The numerous regulatory processes involved pose significant barriers to innovative drug development, which is compounded by high clinical trial attrition rates, enhanced pricing scrutiny for new drug approvals and revenue losses resulting from recent and upcoming patent expirations. Additionally, in spite of technological developments in recent years, including the completion of the Human Genome Project, unmet medical needs remain significant and urgent across multiple therapy areas, owing to global health threats such as the obesity epidemic, aging populations and outbreaks of infectious disease.
Over the past two decades expedited drug development initiatives have gained traction as a means to address this conflict. These programs aim to accelerate drug development timelines for the most innovative and promising investigational therapeutics, enabling drugs with the potential to provide substantial clinical improvements over existing therapies to reach the market faster. Drug developers that are granted expedited drug development status for their investigational agents typically benefit from enhanced levels of communication and resource investment with regulatory agencies. For example, regulatory agencies may have more direct involvement in the design of clinical trials, including proposed methods of data collection and use of biomarkers. Drug developers may also be permitted to produce less robust clinical data, enabling them to run fewer, smaller or shorter trials, which can substantially reduce drug development costs.
Regulatory agencies may also accept an investigational drug onto more than one expedited drug development program. For example, the FDA has four expedited drug development initiatives – Fast-Track, Accelerated Approval, Priority Review and Breakthrough Therapy. Although these programs ultimately share the same goal of reducing drug development timelines, there are subtle differences between them. Investigational drugs eligible for Fast-Track status treat serious conditions such as Alzheimer’s disease, AIDS and cancer. The program permits drugs to be approved on the basis of a single Phase II study, which are typically smaller and less expensive than Phase III trials. However, the Accelerated Approval program permits drugs in development for the treatment of serious or life-threatening illnesses to be approved on the basis of surrogate endpoints reasonably likely to predict patient benefit, rather than clinical endpoints, which often require longer timeframes for data collection. Examples include the approval of oncology drugs based on radiographic images of tumors rather than more meaningful endpoints such as mortality. Additionally, under the Priority Review program the FDA commits to the goal of reviewing new drug applications that appear to offer a therapeutic advance over available therapies within six months instead of the standard 10 months. The Breakthrough Therapy designation, however, aims to expedite the development and review of drugs intended to treat serious diseases where the preliminary clinical evidence indicates a substantial improvement over existing therapies on one or more clinically significant endpoint (FDA, 2015; Kesselheim et al., 2015).
Expedited drug development programs reflect industry trends such as the rise of molecularly targeted therapeutics. Increased understanding of the genetic basis of disease has enabled healthcare providers to select the most beneficial treatments for patients based on specific molecular aberrations (Graig et al., 2016). In clinical trials, targeted therapies have often produced large treatment effects in subgroups of patients predicted to benefit from them that far exceed the treatment effects typically observed with marketed therapies. Such effects may be evident even in small early-phase trials, in which case lengthy drug development programs that prolong the time taken for patients to access potentially life-saving or life-altering drugs may be considered unnecessary or even unethical (Sherman et al., 2013). In recent years several targeted therapies have been approved within the oncology therapy area via expedited pathways, including Zelboraf (vemurafenib) for melanoma, Tagrisso (osimertinib) for lung cancer and Ibrance (palbociclib) for breast cancer.
Moreover, health threats and disease patterns evolve constantly, necessitating rapid medical responses. In particular, epidemiology trends for infectious diseases are highly unpredictable owing to the replicative and mutational capacities of the pathogenic micro-organisms responsible for these diseases (Fauci and Morens, 2012). In addition to the pervasive threat of new outbreaks, increased resistance to antimicrobial drugs has led to limited treatment options for some diseases, including strains of tuberculosis and gonorrhea. Consequently, innovative new antimicrobials are urgently required for development.
While the beneficial impacts of shortening drug development timelines are evident, such practices can inevitably compromise patient safety. Post-marketing studies demonstrate that drugs approved via expedited development programs have inferior safety profiles in terms of AEs and serious safety warnings in comparison to those approved via standard review procedures (Olson et al., 2008). Evidence that post-marketing studies requested by regulatory agencies can be delayed or are sometimes not completed at all exacerbates this risk (Kesselheim, et al., 2015).
While prioritizing patient safety may justify long drug development timelines in most cases, many people with serious or life-threatening illnesses for which there are no satisfactory treatments are willing to accept greater uncertainty concerning drug performance for earlier access to treatment (Sherman et al., 2013). However, in some cases regulators have been criticized for granting expedited approval to pipeline therapies too readily. This normalizes usage of expedited approval processes for drugs that are unlikely to address major unmet needs or provide substantial improvements over existing therapies, which potentially compromises patient safety for the sake of minimal improvement over existing treatment options, or even no improvement at all.
A cohort study analysis of drugs approved by the FDA between 1987 and 2014 identified an increase of 2.5% per year in the average number of expedited review programs granted to each newly approved agent. In addition, the proportion of drugs associated with at least one expedited approval program increased by 2.3% per year. Consequently, by 2014, the majority of newly approved drugs were associated with at least one expedited approval pathway, demonstrating that “the exceptions had become more common than the rule.” Furthermore, this trend disappeared when first-in-class drugs were investigated specifically, despite these drugs accounting for approximately one-third of all drug approvals across the study. This demonstrates that increased usage of expedited approval processes is being driven by non first-in-class therapies, which are less innovative and less likely to lead to significant clinical advances than their first-in-class counterparts (Kesselheim, et al., 2015).
Similar findings were obtained from a cohort study that analyzed drugs approved by Health Canada between 1997 and 2012. Only 36.3% of all drugs granted priority review were assessed as innovative by two independent sources, indicating that priority review status is not always a reliable predictor of a drug’s post-market therapeutic value (Lexchin, 2015).
Expedited drug development programs can lead to transformational clinical breakthroughs and represent a counterpoint to traditional high-risk, resource-intensive clinical development programs. In spite of the benefits to patients and industry, inappropriate usage indicates that expedited drug development often does more harm than good. Modifying regulations and criteria to ensure that only the most promising investigational drugs achieve expedited drug development status may help to alleviate this.
Fauci AS and Morens DM (2012). The Perpetual Challenge of Infectious Diseases. The New England Journal of Medicine; 366: 454-461
FDA (2015). Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. US Food and Drug Administration. Available from: http://www.fda.gov/forpatients/approvals/fast/ucm20041766.htm [Accessed on August 30, 2016]
Graig LA, et al. (ed) (2016). Biomarker tests for molecularly targeted therapies: key to unlocking precision medicine. National Academies Press
Kesselheim AS, et al. (2015). Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study. BMJ; 351: h4633
Lexchin J (2015). Health Canada's use of its priority review process for new drugs: a cohort study. BMJ Open; 5(5): e006816
Olson MK (2008). The risk we bear: the effects of review speed and industry user fees on new drug safety. Journal of Health Economics; 27(2): 175-200
PhRMA (2015). Biopharmaceutical Research & Development: The Process Behind New Medicines. Pharmaceutical Research and Manufacturers of America. Available from: http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf
Sherman RE, et al. (2013). Expediting drug development—the FDA's new “breakthrough therapy” designation. New England Journal of Medicine; 369(20): 1877-1880