New FDA Report Cites 22 Drugs That Passed Phase II But Crashed and Burned in Phase III

January 20, 2017
By Mark Terry, BioSpace.com Breaking News Staff

The Trump administration has indicated plans to reform the U.S. Food and Drug Administration (FDA) “to put greater focus on the need of patients for new and innovative medical products.” So far, it hasn’t selected a commissioner for the FDA, although some of the names suggested, such as Jim O’Neil, a venture capitalist, and Balaji Srinivasan, co-founder of genetics testing company Counsyl, have showed indications that they want to focus on drug safety rather than efficacy, perhaps even cutting the need for in-depth Phase III clinical trials.

The FDA just published a study titled, “22 Case Studies Where Phase 2 and Phase 3 Trials Had Divergent Results." Below are the so-called Hall of Shame drugs that showed promise in Phase II, but failed in Phase III.

1. Bitopertin (Roche, . For schizophrenia. Failed to improve the negative symptoms of schizophrenia.

2. Bitopertin (Bristol-Myers Squibb, . For hepatocellular cancer. Failed to improve overall patient survival compared to approved treatment and had unexpected toxicities.

3. Capsaicin Topical Patch, Qutenza (NeurogesX, ). To treat HIV-associated nerve pain, with previous approval for treatment of shingles-associated nerve pain. Lack of efficacy compared to control groups.

4. Darapladib (GlaxoSmithKline, .) As an add-on to statins for cardiovascular disease in patients with a prior heart attack. Failed for lack of efficacy, despite promising biomarker evidence in Phase II.

5. Dexmecamylamine (Targacept, / AstraZeneca, . For add-on treatment of depression. No more effective than placebo in Phase III trials for treatment of depression.

6. Exhale Drug-Eluting Stent (Broncus Technologies). For reduction of shortness of breath in emphysema patients. Statistically significant results in Phase II, but failed to improve lung function or symptoms in Phase III.

7. Experimental HSV-2 Vaccine (Chiron, now Novartis Vaccines & Diagnostics). To prevent genital herpes. Positive biomarker results in Phase II, did not prevent genital herpes in Phase III.

8. Gluatmic Acid Decarboxylase Vaccine (Diamyd Medical). For the preservation of insulin secretion for patients with recent-onset type 1 diabetes. Promising results in Phase II, but in the Phase III trial, did not improve pancreatic function or clinical outcomes.

9. Imiquimod, Aldara 5% Cream (3M, . To treat molluscum contagiosum (MC) lesions in children. Was approved to treat external anogenital warts. Showed promising Phase II results, but in Phase III did no better than placebo.

10. Iniparib (Sanofi, . As an add-on treatment of triple negative breast cancers. Showed promising tumor response and survival in Phase II, but in Phase III did not improve survival.

11. Lithium (King's College London, UK). Already a treatment for bipolar disorders, was being tested as an add-on treatment to delay disease progression of amyotrophic lateral sclerosis. Showed positive effects on disease progression and survival in Phase II, but in Phase III did not improve survival, health status or quality of life.

12. MAGE-A3 Vaccine (GlaxoSmithKline, . For non-small cell lung cancer (NSCLC). Proof of concept trial was promising, but showed no clinical benefit compared to placebo in Phase III.

13. NicVAX Vaccine (Nabi Biopharmaceuticals, . For smoking cessation. Promising Phase II, but in Phase III the abstinence rate was similar to placebo.

14. Velimogene Aliplasmid, Allovectin-7 (Vical , . For metastatic melanoma. In Phase II, showed evidence of tumor shrinkage. In Phase III, reduced tumor size in significantly fewer patients than two other marketed drugs.

15. Olanzapine Pamoate, Zyprexa Relprevv (Eli Lilly, . Evaluated for long-acting injection treatment for schizophrenia. Already approved as an oral short-acting treatment for schizophrenia. In Phase III, identified serious safety risks.

16. Aliskiren, Rasilez, Tekturna (Novartis, . Evaluated as an add-on treatment for prevention of congestive heart failure (CHF) complications. Previously approved for hypertension. Positive results in an proof of concept study, but in the Phase III trial adding aliskirin to standard therapy, did not cut cardiovascular-related death or CHF re-hospitalization, and showed an increase in kidney failure and low blood pressure.

17. CoStar Drug-Eluting Stent (Conor Medsystems). To cut heart attack risk in patients with coronary artery disease. Although approved in Europe and had positive results in a small trial, patients who received it in Phase III trials had worse outcomes than those receiving different stents.

18. Figitumumab (Pfizer, . Evaluated as an add-on treatment of advanced non-small cell lung cancer (NSCLC). Showed promise in Phase II, but in Phase III failed to improve survival. Also, in one combination with another regimen, increased serious adverse events and deaths.

19. Recombinant Factor VIIa, NovoSeven (Novo Nordisk, . Evaluated for decrease of intracerebral bleeding and hematoma size in stroke patients. Already approved for hemophilia. Showed positive Phase II results, but in Phase III, patients didn’t show clinical benefits, but did have an increase incidence of serious events compared to patients receiving the placebo.

20. Semagacestat (Eli Lilly, . For Alzheimer’s disease. Showed promising biomarker results in Phase II, but the Phase III trial was ended early because patients receiving the drug had worsened cognition, worse functional status, and an increased risk of skin cancer.

21. Torcetrapib (Pfizer, . For the prevention of cardiovascular events in patients with a history of cardiovascular disease or type 2 diabetes. Showed improved cholesterol levels in Phase II trials, but in Phase III it increased mortality and cardiac events compared with placebo.

22. V710 Vaccine (Intercell--now Valneva / Merck, . V710 Vaccine (Intercell (now Valneva)/Merck, MRK). Evaluated as a vaccine to prevent Staphylococcus aureus infection. Showed promise in Phase II, but the Phase III clinical trial was ended early because of lack of efficacy and the potential risk for serious adverse events and death.

John Carroll, writing for Endpoints News, writes, “Some on the libertarian side have said they want to simply toss out the gold standard on efficacy and safety altogether, excoriating the old rules of market engagement. That toxic argument raises some important questions about each stage of drug development. And there’s a new report out from the FDA that covers just what you can miss if you cut Phase III out altogether.”