Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

FDA’s recently issued guidelines pull from more than 20 years of research and clinical experience.

Cancer immunotherapy has come a long way in the past few decades. When researchers began working on this technology, there were no FDA regulations in place to direct R&D. Over time the agency drafted and issued guidelines for various areas of cell therapy, and finally in October 2011, put forth guidance specific to cancer vaccine development.

FDA’s move came over a year after a significant milestone was reached in the field of cancer immunotherapies. In May 2010, the first cell-based autologous cancer vaccine was sanctioned in the U.S.: Dendreon’s Provenge (Sipleucel T) for advanced prostate cancer. “When I started this work in the early 1990s, no IND was required because cellular therapy was not regulated by the FDA,” Edgar Engleman, M.D., co-founder of Dendreon, told GEN; Dr. Engleman discovered the potential of harnessing the body’s immune cells to treat cancer while he was at Stanford University School of Medicine.

“I did apply for and received IRB approval at Stanford, but this was before the company got going,” he recalled. “We were performing very small clinical studies with dendritic cells in patients with cancer. Because we were giving patients back their own cells, the general expectation was that the approach was going to be safe, and this proved to be the case.”

Subsequent to these early experiments, he explained, the FDA decided to regulate cellular therapies and created new guidelines intended primarily to assure product sterility. “While the guidelines may be welcome by some and certainly provide an additional measure of safety, as a consequence of these regulations the cost of preparing cellular therapies has skyrocketed, making it impossible for most academic-based investigators including ourselves to perform the types of clinical experiments we did almost 20 years ago.” Dr. Engleman was referring to one aspect of the fairly agonizing regulatory process that would eventually be required for FDA’s approval of Provenge: preparation of autologous cells under GMP conditions.

Differentiating Immunotherapies from Chemotherapies

The agency’s approval of Dendreon’s vaccine marked a significant turning point for cancer vaccines, a treatment modality that had developed a bad reputation after repeated high-profile clinical failures. Provenge as well had its shares of clinical trial agony. In 2007, FDA declined to approve the vaccine based on results from a 127-patient Phase III trial (D9901) in which Provenge improved median survival by 4.5 months and reduced risk of death by 41%. That decision contravened a 17–0 vote in favor of approval from FDA’s Cellular, Tissue and Gene Therapies Advisory Committee.

Provenge was eventually approved, three years later, based on a separate Phase III study (IMPACT) that involved 512 men. It showed that Provenge extended median survival by 4.1 months and reduced the risk of death by 22.5%.

In commenting on the long path to approval that Dendreon has had, Manish Singh, Ph.D., president and CEO of Immunocellular Therapeutics, told GEN, “immunotherapy is inherently different from chemotherapy drugs that have been developed in the past. While chemotherapy has typically relied on tumor reduction to demonstrate activity, immunotherapy treatments have different biological effects and therefore require different measures of antitumor effect.”

He felt that the guidance will prove “very helpful as it differentiates between the immunotherapy and chemotherapy paradigms, focusing on a clear approval pathway for immunotherapy products.”

Leveraging FDA Guidelines

Provenge’s development path provided a basis, in large part, for vaccine developers and regulators struggling to understand appropriate endpoints and biological markers for therapeutic cancer vaccine trials. FDA’s “Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines” was issued in October 2011, a year and five months after Provenge’s approval. “Although the FDA guidelines are new,” Dr. Singh remarked, “they are backed by more than two decades of research and clinical experience, to which members of our scientific leadership meaningfully contributed.”

Dr. Singh offered these tips based on the guidelines: “We believe that conducting a randomized Phase II clinical trial early on is important to understanding clinical outcomes. We also agree that while progression-free survival is an important secondary endpoint, overall survival ought to be the primary indicator of therapeutic efficacy in most immunotherapy trials.

“Our current Phase IIb trial for glioblastoma adheres to these guidelines as we are primarily evaluating overall survival, using disease-free survival as a secondary endpoint.” ImmunoCellular Therapeutics’ lead product candidate, ICT-107, is an autologous dendritic cell-based vaccine.

Carlos F. Santos, Ph.D., svp, product development and regulatory affairs for cancer vaccine developer Biovest told GEN, “We’re encouraged with regard to the current U.S. regulatory environment for targeted oncology therapies with the FDA seemingly becoming increasingly flexible, evidenced by multiple recent approvals, even approving such drugs based on highly positive Phase II data alone.

“Our targeted cancer therapy, BiovaxID, is an autologous active immunotherapy,” Dr. Santos explained. “We are prepared to present what we believe is a compelling case in favor of its approval for the treatment of non-Hodgkin lymphoma.”

Besides Biovest, Immunocellular Therapeutics, and Dendreon, significant players in the cancer vaccine field include Bavarian Nordic and Prima BioMed. Bavarian Nordic’s Prostvac is a nonautologous candidate for advanced prostate cancer in Phase III development. Prima BioMed is investigating CVac, a personalized autologous dendritic cell therapy, as a treatment for ovarian cancer in Phase II.

These companies as well as researchers in earlier stages of R&D for cancer vaccines will fair best if they follow the regulatory guidance provided by the FDA. By lessening the uncertainty that surrounds the development path for this completely novel class of cancer therapies, the agency hopes to incentivize more innovation. On the flip side, though, scientists will have to bear the financial burden associated with increased regulation. Nonetheless, as evidence mounts with regard to biomarkers for clinical response to cancer immunotherapies, developers will have another piece of the puzzle to help make better decisions on clinical development as well as design.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

Previous articleDrug Developer Pursues an Open-Source Approach in Designing Clinical Trials
Next articleBioConnections Licenses Hebrew University’s Rapid MDR Infection Test Kits