Earlier this month saw President Trump call for an overhaul of the FDA and the way it approves drugs, in particular accelerating the drug approval process. News media outlets have been quick to highlight that Jim O’Neill, a potential candidate to run the FDA under the Trump administration, has advocated that companies need not show their drugs are effective in order to have them approved; O’Neill has commented in the past that safe drugs could be brought to market, and prove their efficacy later.

If such a policy were to be implemented by the FDA, what would happen? At Decision Resources Group, our experts have gathered together some historical examples from across medicine that show the potential pitfalls of this approach:
Fovista—Wet Age-Related Macular Degeneration

Number of eligible US patients: 360,000 (total number of diagnosed and drug-treated patients with wet AMD in the US at the time of forecasted launch [2018]).

Ophthotech/Novartis’s Fovista, a platelet-derived growth factor (PDGF) inhibitor, was expected to be the first therapy within its class approved for the treatment of wet age-related macular degeneration (AMD). PDGF inhibitors were anticipated to enhance the efficacy of vascular endothelial growth factor (VEGF) inhibitors, the current standard of care for wet AMD; some patients do not adequately respond to VEGF inhibition alone. Following positive Phase IIb trial results for Fovista in combination with Roche/Genentech’s VEGF inhibitor Lucentis versus Lucentis monotherapy, three Phase III trials began to evaluate intravitreal-administered Fovista in combination with Lucentis, Regeneron’s Eylea, or off-label Roche/Genentech’s Avastin in the treatment of wet AMD. However, in December 2016, Ophthotech announced that Fovista did not meet the primary efficacy end point in the two Phase III trials examining Fovista in combination with Lucentis compared with Lucentis monotherapy. These trials were subsequently terminated early—they had originally been planned to run for 24 months—as were the Phase II expansion trials; the third Phase III trial evaluating Fovista in combination with Avastin or Eylea compared with Avastin or Eylea monotherapy remains ongoing, although physician and investor confidence in the success of this final Phase III trial has plummeted, along with hope for the efficacy of PDGF inhibitors in wet AMD.


Solanezumab—Mild Alzheimer’s Disease

Number of eligible U.S. patients: 1.3 million (total number of diagnosed patients with mild AD in 2015).

Alzheimer’s disease (AD) is an area of considerable unmet need with no drugs that can delay or even slow the inexorable cognitive decline and a rapidly aging population. Until just a few months ago, Eli Lilly’s solanezumab, an amyloid targeting monoclonal antibody, was poised to be the first disease-modifying therapy (DMT) for AD; overcoming its own checkered development history and a string of previous failed DMTs. In two Phase III trials in more than 2,000 mild to moderate AD patients, completing in 2012, solanezumab failed to meet the coprimary endpoint of cognition and function. However, a pooled analysis of only mild patients from these two trials demonstrated a reduction in decline of both cognition and function. Solanezumab was also the first drug to demonstrate disease modification through a delayed-start analysis; mild patients who initiated solanezumab from the start of the trial showed less decline than placebo patients re-randomized to solanezumab in the extension study. Given these data, and the overall clean safety profile of the drug, Lilly launched a third Phase III trial in mild AD patients only, and a subsequent trial in prodromal AD patients. However, in November 2016, Lilly reported solanezumab once again failed to meet its primary endpoint in the third Phase III trial and discontinued development of the drug for mild and prodromal AD. Given the IV delivery profile of this drug and its projected high cost, had solanezumab come to market before it completed its clinical trial program, a meaningful number of patients and their families would have faced significant practical and financial hardships, for a drug that offered them little more than false hope.


Epratuzumab – Moderate to Severe Systemic Lupus Erythematosus (SLE)

Number of eligible U.S. patients: 85,000 (moderate to severe SLE patients [without severe active renal and severe active CNS manifestations] in 2015)

UCB’s epratuzumab demonstrated a very promising risk/benefit profile in a 12-week Phase IIb trial in patients with moderate to severe SLE (EMBLEM). In terms of safety, the rates of adverse events and serious adverse events were similar across epratuzumab groups and the placebo group, an important achievement for a novel therapy intended as an add-on treatment to the current intrinsically toxic standard of care agents. From an efficacy standpoint, the drug demonstrated a placebo-adjusted response rate of up to 24.8% (using the BICLA index as an outcome measure), which was viewed as very substantial by thought leaders in the field. Only one drug, GlaxoSmithKline’s Benlysta, has been approved for SLE by the FDA in over fifty years, and even based on Benlysta’s Phase III performance – it evoked a placebo-adjusted response rate of 12% (using the SRI as an outcome measure) – this drug is still viewed as only moderately efficacious by rheumatologists treating SLE. Thus, epratuzumab was poised to enter a market with a high level of unmet need and, based on its Phase IIb performance, to offer a substantial improvement over Benlysta and other older drugs used for the treatment of SLE. However, when further tested in the longer (48 weeks) and larger Phase III trials (EMBODY 1 and EMBODY 2), epratuzumab was only able to achieve a placebo-adjusted response rate of 0.6-5.7%, suggesting virtually no improvement in disease activity compared to the standard of care. Had epratuzumab come to the SLE market on the strength of its Phase II data alone, and given the high unmet need in the SLE market, it would have potentially cost patients, insurance companies and the government hundreds of millions of dollars per year. Patients receiving the drug would have been burdened with unnecessary frequent intravenous infusions, which could have led to unpleasant infusion reactions and certainly required these patients to spend several hours in the hospital in order to receive the drug dose (they would also have been denied treatment with other potentially more efficacious agents). Even dismissing any potential safety concerns, use of epratuzumab would have added an additional burden on the healthcare facilities administering the drug with little evidence to justify these costs.


Bardoxolone methyl – Diabetic kidney disease (DKD)

Number of eligible U.S. patients: 7 million (diabetic nephropathy prevalence in 2015)

In Phase II studies, Reata’s bardoxolone methyl was found to increase estimated glomerular filtration rate, an important marker measuring kidney function. These positive results were met with excitement; physicians and investors viewed bardoxolone methyl as a potential blockbuster, given the lack of efficacious therapies able to halt disease progression and significant unmet need. Patients with diabetic nephropathy face high risk for progression to end stage renal disease (ESRD), also known as kidney failure. Unfortunately, the Phase III study (BEACON) was terminated early due to safety concerns – chiefly, a greater number of cardiovascular-related deaths and hospitalizations occurred among patients treated with bardoxolone methyl. In addition, the primary endpoint was not achieved; bardoxolone methyl did not lower the risk of ESRD or death from cardiovascular causes.


Torcetrapib – Dyslipidemia and Reduction of CV Risk

Number of eligible U.S. patients: 40,000,000 (secondary CV risk population)

There is a vast amount of evidence showing that low levels of HDL-cholesterol (the ‘good’ cholesterol) and high levels of LDL-cholesterol (the ‘bad’ cholesterol) are linked to an increased risk of atherosclerosis and CV disease. So, when the Phase II data for Pfizer’s CETP inhibitor torcetrapib demonstrated improvements in both parameters, without any safety concerns, there was genuine excitement that the next big breakthrough in CV disease prevention was imminent. However, these hopes were crushed when the 15,000-patient Phase III ILLUMINATE trial of torcetrapib was terminated early after it emerged that the rate of deaths and CV events was higher in those patients receiving the novel therapy. The full analysis of the trial demonstrated no beneficial effect on atherosclerosis and an increase in blood pressure with torcetrapib. Without the Phase III data, approval of torcetrapib could have meant patients trading improved lipid profiles for hypertensive CV events.


Zydelig – Chronic Lymphocytic Leukemia

Number of eligible U.S. patients: 19,000 (drug-treatable second and third-line CLL patients in 2015)

In July 2014, the FDA approved Gilead’s Zydelig (a PI3K-δ inhibitor) in combination with rituximab for the treatment of chronic lymphocytic leukemia patients who have received at least one prior therapy.  Approval was based on data from one Phase III placebo-controlled trial which was stopped early based on advice from the Independent Data Monitoring Committee owing to a positive progression-free survival result. At the same time, Zydelig monotherapy was also granted accelerated approval for the treatment of relapsed or refractory follicular lymphoma and small lymphocytic leukemia patients (for those who have received at least two prior therapies). Accelerated approval was based on overall response rate (benefits in patient survival or disease-related symptoms had not been established). Some serious safety concerns were described at the time of approval, but additional trial data reported from unapproved settings and combinations highlighted significant safety concerns. In March 2016, six international clinical trials assessing Zydelig in combination with other agents were stopped and eventually terminated, following reports of an increased rate of serious adverse events, including deaths. Larger, longer, and more robust trials could have identified these safety concerns earlier, and measures put in place to reduce risks. Both the FDA and the EMA have since issued statements, warning healthcare professionals of the serious adverse events.


Kadcyla – HER2-Positive Gastric and GEJ Adenocarcinoma

Number of eligible U.S. patients: 1,870 (second-line metastatic HER2-positive patients in 2015)

Agents which are proven safe and efficacious for the treatment of one tumor type are often evaluated in other tumor types. However, success in one indication doesn’t necessarily predict success in others. Roche’s Kadcyla (a HER2-targeted toxin-conjugated monoclonal antibody) is approved to treat HER2-positive metastatic breast cancer patients who have previously received Herceptin and a taxane.  Based on the proof of concept that Herceptin is safe and effective in both breast cancer and gastric cancer, Roche intended to secure approval of Kadcyla in HER2-positive advanced gastric and GEJ adenocarcinoma in 2015. However, in November 2015 the company announced that Kadcyla had failed in the pivotal Phase II/III GATSBY trial (evaluating Kadcyla in the second-line setting for gastric and GEJ adenocarcinoma patients). Although early clinical data for Kadcyla in gastric cancer were lacking, the similarities between Herceptin and Kadcyla and the fact that Herceptin was efficacious in gastric cancer led many thought leaders to believe that Kadcyla would demonstrate an overall survival benefit; however, this was not the case. Making a leap of faith and prescribing Kadcyla without proven efficacy benefits, even when similar agents have manged to make that leap, could have denied gastric cancer patients alternative effective treatments.


Zolinza – Myelodysplastic Syndrome

Number of eligible U.S. patients: 12,000-14,000 (diagnosed prevalent high-risk MDS patients in 2016)

Vorinostat (Merck’s Zolinza) is a histone deacetylase (HDAC) inhibitor that was in trials for MDS as a combination therapy with first-line injectable azacitidine (Celgene’s Vidaza). Vorinostat + azacitidine demonstrated 67-73% response rates across three dose-finding cohorts (total n = 33) in a 2013 Phase I/II study in higher-risk MDS patients. These results were encouraging because typical response rates to first-line agents in this difficult population are 30-40%. However, Phase III testing conducted in 2014 showed that vorinostat provided no additional benefit compared to azacitidine alone (22% [n = 91] in combination vs. 36% response rate with azacitidine only [n = 92]). Development of vorinostat in MDS has largely been discontinued, and KOL opinion on HDAC inhibitor use in MDS treatment has soured due to this high profile failure.

The above examples speak for themselves in terms of the potential risks to patients as well as costs to healthcare insurers, but there are some other points to consider too.

  • Would this approach gain any traction among prescribers? Despite the earlier access to novel drugs, physicians may not be willing to prescribe agents that do not have enough data behind them. Doctors are accustomed to having data from large trials to help them inform their treatment decisions, and may be unwilling to turn their back on this engrained practice. In this scenario, the pressure from patient requests for drugs could be much harder for doctors to manage. 
  • How will we follow up on the efficacy (and safety) of drugs that come to market so quickly? With the criteria for approval slackened, follow-up of new agents could become harder. Large Phase III clinical trials monitor the effect of drugs in a controlled way, and we can’t rely on real-world follow-up to provide the same level of information. There is also the potential that earlier approval of drugs in this way would hurt clinical trial recruitment, as therapies that would have previously have been deemed experimental will be available on prescription, possibly discouraging patients from taking part in trials. 
  • What is a “safe” drug, anyway? Demonstrating safety in a Phase I or even Phase II trial isn’t always enough, as some of the above examples show. Sometimes, it can take thousands of patients to be treated before an incredibly rare but very serious side-effect is detected. We can’t even extrapolate between diseases, for example in oncology some drugs are safe in certain cancer types and not in others.

In short, randomized controlled Phase III trials are a great thing; they provide robust information upon which to base drug approvals and treatment decisions. We have too many examples of drugs that looked promising in earlier trials but turned out to not work in Phase III investigations (the list of contenders to be included in this article was large) to waive the need for large, randomized, controlled studies before drugs come to market.

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