Originally published Jun 10th 2015 by Scott Milligan on linkedin.com

In May 2015 the House Energy and Commerce Committee approved the 21st Century Cures Act, legislation intended to increase access of potential cures to patients through a revisiting of processes from drug discovery through approval to access and delivery. A section of that act addressed the role of real-world evidence relative to randomized clinical trials in the FDA approval process. Not surprisingly, concern has been voiced over the validity of observational studies and the use of registries as evidence in assessing efficacy of an intervention (Avorn J. and Kesselheim A.S. N Engl J Med. 2015 Jun 3).

Randomized clinical trials are (currently) without comparison for establishing the efficacy of treatment in an idealized setting. Unfortunately, the idealized setting may only represent a fraction of the patient population. In contrast, real-world evidence is representative of the larger population but may be influenced by factors unrelated to treatment, which may mask or enhance results, especially when the treatment effect is small. Both clinical trial and real-world studies require validated methodological approaches (visit ISPOR, STROBE, AHRQ for details) and for general acceptance, are subject to the same critical scrutiny of the peer review process. When sound processes are in place, less structured, more representative real-world studies complement more structured, less representative randomized clinical trials. An outstanding example of this can be found from studies in Hepatitis C.

Real-world evidence level sets clinical trial expectations

The approval of Sovaldi at the end of 2013 was a game changer for the treatment of Hepatitis C. For the first time, cure rates approaching and exceeding 90% were obtained for different variations (genotypes) of the Hepatitis C virus (see A Brief History of Hepatitis C. HCSP FACT SHEET Mar 2015). A Sovaldi regimen used in genotype 1 HCV, the variant which is most prevalent in the US affected population, cured 89% of previously untreated patients. Eleven months after Sovaldi approval, results of Sovaldi use in real-world genotype 1 HCV was first reported (Dieterich D, et al. Hepatology 2014; 60: 46). The final results in the treatment naïve genotype 1 group revealed a reduced, though still impressive cure rate of 80% (Dieterich D et al. Gastroenterology 2015; 148(4): S1001). Importantly, most of the difference was attributable to realities of treatment in an uncontrolled setting. In the real-world, more patients stopped therapy prematurely and a group of patients were lost to follow up, i.e. they didn’t return their physicians phone calls or moved away and couldn’t be reached. Removal of these issues results in a success rate nearly identical to that reported in the clinical trial (Figure 1).

These findings from real-world data level set expectations obtained from the randomized clinical trial and provide clear guidance to providers; in order to maximize therapy potential, healthcare stakeholders must address the challenges of continued patient engagement.

Real-world evidence provides efficient and essential vetting of FDA assumptions

When the remarkable results with Sovaldi were first obtained, the FDA faced the challenge of whether to limit approval to only those groups studied in the clinical trials or to allow broader use based upon a series of assumptions. The specific patients in question were those who had previously been treated for hepatitis C but were not cleared of the virus. To estimate likely efficacy in this population, the FDA used several approaches, all of which included assumptions based on historical treatments (Mishra P, et al. Gastroenterology 2014; 147:1196). Though the different assumptions yielded a wide range of estimated cure rates, the analyses indicated that the Sovaldi regimen was likely similar if not superior to historical treatments in efficacy and offered a less toxic treatment option. For that reason, the FDA approved use of this Sovaldi regimen in both treatment naïve and treatment-experienced genotype 1 patients.

Real-world evidence from treatment-experienced patients indicated a cure rate of 74%. By only examining patients that completed the Sovaldi treatment, the cure rate increased to 81% (Dieterich D, et al. Gastroenterology 2015; 148(4): S1001). These rates are in line with the higher estimates from the FDA, and validate the FDA’s decision to approve use of this regimen in this population, despite lack of data from a randomized clinical trial (Figure 2).

More broadly, these results suggest that rapid assessment of populations not represented or under-represented in clinical trials may be gathered through real-world evidence, and with logical analyses, shorten decisions and/or refine approaches to making therapies available to those in need.

Real-world evidence is fundamental to improving care in the 21st century

These examples from Hepatitis C show how real-world evidence may be complementary to randomized clinical trials in the FDA decision process and beyond, where real-world evidence is critical to translating efficacy (optimal results) into effectiveness (realized results). In diseases such as Hepatitis C, where cure is a possibility for most patients, real-world evidence may also reveal non-clinical hurdles such as delays in coverage, convoluted distribution requirements, formulary restrictions or denied access to care (see Younossi Z, et al. Gastroenterology 2015; 148(4): S1090). In other diseases, where cure or living a normal life with disease is unlikely at present, real-world evidence may speed progress towards improved outcomes.

Expectations for care continue to shift. Different healthcare stakeholders are demanding that treatment costs reflect effectiveness (Loftus P, Wall Street Journal May 26th 2015, Wasserman E, FiercePharma Feb 24th 2015). Patient input as to measures that matter is not only considered, but actively sought (Selby J, Health Affairs Blog Mar 25th 2014). In short, healthcare is more rapidly moving towards a holistic approach; an approach reflected in the 21st Century Cures Act and one that is not possible without real-world evidence.

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Figure 1. Cure (SVR12) rates in previously untreated patients with genotype 1 HCV. Note that this graph as presented is an oversimplified comparison of these studies. To obtain and assess the data in greater detail, please visit the original sources: Real-world data from Dieterich D, et al. Gastroenterology 2015; 148(4): S1001, Clinical Trial Data from Lawitz E, et al. N Engl J Med. 2013 368(20): 1878.

Figure 2. Estimated and actual cure (SVR12) rates in patients previously treated for genotype 1 HCV. Note that this graph as presented is an oversimplified comparison of these studies. To obtain and assess the data in greater detail, please visit the original sources: Real-world data from Dieterich D, et al. Gastroenterology 2015; 148(4): S1001. FDA analyses from Mishra P, et al. Gastroenterology 2014;147:1196.

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Notes and Resources

The views expressed here do not necessarily reflect those of my current or former employers.

The Sovaldi regimen discussed above is 12 week pegylated interferon + ribavirin + Sovaldi. See the full prescribing details at www.sovaldi.com.

A Brief History of Hepatitis C. HCSP FACT SHEET Mar 2015. Accessed Jun 6th 2015 at http://hcvadvocate.org/hepatitis/factsheets_pdf/Brief_History_HCV.pdf.

Avorn J. and Kesselheim A.S. The 21st Century Cures Act — Will It Take Us Back in Time? N Engl J Med. 2015 Jun 3 [Epub]. Accessed Jun 6th 2015 at http://www.nejm.org/doi/full/10.1056/NEJMp1506964.

Bacon BR, et al. Efficacy of sofosbuvir and simeprevir-based regimens for HCV treatment-experienced GT1 Patients in a real-life setting; data from the TRIO network. Hepatology 2014; 60(S1): 672A.

Dieterich D, et al. Final evaluation of 955 HCV patients treated with 12 week regimens containing sofosbuvir +/- simeprevir in the TRIO network; Academic and community treatment of a real-world, heterogeneous population. Gastroenterology 2015; 148(4): S1001.

Dieterich D, et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network; Academic and community treatment of a real-world, heterogeneous population. Hepatology 2014; 60: 46.

Express Scripts says controlling cancer-drug costs a tough new focus. Apr 29th 2015. Accessed Jun 6th 2015 at www.reuters.com/article/2015/04/29/us-express-scr-cancer-idUSKBN0NK1N620150429.

FDA approves Sovaldi for chronic hepatitis C. Dec 6th 2013. Accessed Jun 6th 2015 at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm377888.htm.

Lawitz E, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 368(20): 1878–87.

Loftus P. New Push Ties Cost of Drugs to How Well They Work. As drug costs rise, Express Scripts seeks new payment deals for some cancer medications. Wall Street Journal May 26th 2015. Accessed Jun 6th 2015 at www.wsj.com/articles/new-push-ties-cost-of-drugs-to-how-well-they-work-1432684755.

Mishra P, et al. FDA Perspective on Sofosbuvir Therapy for Patients With Chronic Hepatitis C Virus Genotype 1 Infection Who Did Not Respond to Treatment With Pegylated Interferon and Ribavirin. Gastroenterology 2014; 147:1196–1200.

Selby J. PCORI’s Research Will Answer Patients’ Real-World Questions. Health Affairs Blog Mar 25th 2014. Accessed Jun 6th 2015 at healthaffairs.org/blog/2014/03/25/pcoris-research-will-answer-patients-real-world-questions/.

The 21st Century Cures Act: UNANIMOUSLY APPROVED. May 21st 2015. Accessed Jun 6th 2015 at energycommerce.house.gov/press-release/21st-century-cures-act-unanimously-approved#sthash.VdkDVqGK.dpuf.

Tsai N, et al. Comparison of sofosbuvir +/- simeprevir in heterogeneous, real-world populations of HCV patients over 70 years; data from the TRIO network. Gastroenterology 148(4): S1085.

www.ahrq.gov

www.ispor.org

www.pcori.org

www.strobe-statement.org

www.triohealth.com

Wasserman E. Turning to Twitter, MD Anderson doc launches campaign against cancer drug prices. FiercePharma Feb 24th 2015. Accessed Jun 6th 2015 at www.fiercepharma.com/story/turning-twitter-md-anderson-doc-launches-campaign-against-cancer-drug-price/2015-02-24.

Younossi Z, et al. Evaluation of access to care in patients prescribed sofosbuvir-containing regimens: data from the TRIO network. Gastroenterology 148(4): S1090.