Andrew Kinley, Ph.D.

	The randomized clinical trial as we know it today-composed of three sequential, stand-alone pre-approval phases-has not changed structurally for decades. But the rapid rise of targeted drugs and biologics in oncology, and immuno-oncology in particular, has spurred sponsors and the US Food and Drug Administration (FDA) to innovate, leading to the creation of a variation to the typical trial design that can include multiple expansion cohorts. Unlike traditional trial designs, a multiple expansion cohort trial enables sponsors who spot strong, positive responses to an investigational drug during early stages of testing to expand the trial using additional single-arm studies to gather pivotal data quicker and speed the drug’s path to approval. These designs can cut the typical development times for conventional trials in half.  

	The intent of this design is to substantially compress development times for conventional trials. According to an FDA draft guidance released in August 2018, which focuses on oncology drugs and biologics, this could happen by conducting first-in-human (FIH) trials with an initial dose-escalation phase that also contains three or more additional patient cohorts with cohort-specific objectives.

 As the draft guidance explains, the objectives of these expansion cohorts can include:

	· Assessment of anti-tumor activity in a disease-specific setting

	· Assessment of a reasonably safe dose in specific populations (e.g., pediatric or elderly patients or patients with organ impairment)

	· Evaluation of alternative doses or schedules

	· Establishment of dose and schedule for the investigational drug administered with another oncology drug

	· Evaluation of the predictive value of a potential biomarker

How Multiple Expansion Cohort and Traditional Trials Differ

	This approach is a dramatic departure from the classic method of conducting clinical trials. Traditionally, drugs must undergo Phase I for safety, tolerability and dose testing; Phase II to determine efficacy and side effects and to accrue additional safety data; and Phase III for demonstrating whether a product offers a treatment benefit to a specific population, often compared to standard therapy.

 This step-by-step methodology provides the basis for regulatory approval, and typically takes about eight to ten years to complete.

There are alternatives, however. The FDA offers various types of accelerated therapeutic development and review processes, namely Fast Track, Breakthrough Therapy, Accelerated Approval and Priority, with each serving a different purpose, and focusing largely on meeting medical needs of patients.

 But the continuum is now growing to include multiple expansion cohort trials of oncology drugs and biologics, which measure pharmacology and early efficacy simultaneously in a proof-of-concept stage. This is followed by establishing dosing and further efficacy testing in therapeutically-aligned or mutation-defined patient cohort expansions that are either single-arm or randomized. As stated in the FDA draft guidance, not all therapies are suited for this trial design, and sponsors should only use this approach for patients with serious diseases for whom there is no curative therapy available. Moreover, sponsors should provide a robust rationale for using this type of trial (Chart 1).

	These expanded cohorts enable investigators to design efficient trials based on analyses of the interim data. An investigator can assess which drug doses are working in which patient populations and expand or drop certain cohorts accordingly. This flexibility prevents investigators from having to complete failing treatment arms, and it also allows them to add more patients to treatment arms in which the investigational drug shows efficacy, thereby improving the chances that a development plan will succeed.

	Keytruda® (pembrolizumab), a successful immunotherapy, first achieved regulatory approval using a multiple expansion cohort trial.

 Merck started a first-in-human study in 2011 in a small group of patients with advanced solid tumors to test the biologic’s safety.

 By the end of the trial, Merck had added 

, bringing the total number of patients enrolled to 1,200.

Early results showed that patients with metastatic melanoma and non-small cell lung cancer (NSCLC) responded positively to the biologic, and this opened the door to further evaluation of efficacy, dosing, and potential predictive biomarkers. Only three years after the trial’s inception, the FDA approved Keytruda for advanced, unresectable or metastatic malignant melanoma with disease progression after prior treatment with Yervoy (another immunotherapy), and in 2015, they followed with an approval for chemo-resistant, advanced NSCLC.

The Rising Popularity of Multiple Expansion Cohort Trials

	Sponsors and regulators alike are embracing the advantages of these multiple expansion cohort clinical trials for cancer therapeutics. 

 conducted by a multi-institution consortium of hospitals, academia, research institutes, pharma, and the government examined 1,786 Phase I/II studies enrolling 100 or more patients that were presented at the American Society of Clinical Oncology (ASCO) annual meetings from 2010 to 2017.

 The findings, presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, determined that 65 percent of the 51 “seamless” (multiple expansion cohort) trials presented data after 2014, indicating a rise in popularity in recent years. Those 51 trials accounted for 15 percent of patients who participated in oncology trials during that time, included up to 13 expansion cohorts, and involved 50 investigational new drugs, including targeted therapies, immunotherapies, antibody-drug conjugates, and chemotherapies. Corroborating this uptick, in 2016, the FDA Office of Hematology and Oncology Products (OHOP) reported they had received 40 active commercial investigational new drug (IND) applicationsfor large, FIH oncology trials that included seamless designs.

	Not only are seamless trials increasing in popularity, but they are also potentially more successful, on average, than traditional trials. According to the ASCO study, an estimated 5 percent of oncology drugs that are tested in humans ultimately achieve approval, but 16 percent of trials using seamless designs received accelerated approval from the FDA.

 Another analysis revealed the value of expansion cohorts in Phase I trials: subsequent Phase II trials were twice as likely as Phase II trials with no expanded cohorts to succeed if the preceding Phase I trial included an expansion cohort of two to 20 patients.

 Furthermore, there was a statistically significant difference in the approval of drugs within five years among drugs in Phase I trials with expansion cohorts as compared to those without one [19% vs 5%, HR 4.4, 95% CI 2.2-8.8, p < 0.001)]. More research is required to understand why seamless trials result in a higher approval rate, with multiple variables requiring exploration, such as selection bias of therapy, a lower regulatory bar for approval, or an increase in development strategy options.

The Limitations of Multiple Expansion Cohort Trials

	Since multiple expansion cohort trials move so quickly through the development pathway, the FDA does not have time to consider the long-term clinical benefit and safety of new therapies. Further, they cannot derive deep understanding of a therapy’s efficacy from early expansion trial data as these data are typically collected from single-arm studies. But although it is more challenging to collect survival and safety profiles compared to standard therapies, the FDA will still approve many of these therapies, which can increase the risk to patients. In fact, the FDA has even suggested ways to work around accelerated trial timelines. For example, one way to gauge an investigational product’s efficacy in a short timeframe is to use surrogate measures of long-term clinical benefit, such as the response rate to a therapy or progression-free survival.  

	Under the accelerated approval guidelines, the FDA cites an 

 whereby instead of requiring data showing a cancer therapy extends patient survival, the Agency may base approvals on a surrogate endpoint, such as tumor shrinkage, that is “reasonably likely to predict a clinical benefit.” This metric takes less time to establish, but still requires a post-approval confirmatory trial showing the treatment does indeed lead to longer patient survival.

	The Agency addressed the concerns over approving drugs without direct evidence of their long-term safety in its August draft guidance. “Because of the rapid enrollment and evolving nature of the information obtained in these trials,” the guidance states, “large numbers of patients are exposed to drugs with unknown efficacy and minimally characterized toxicity profiles.” To mitigate these risks and safeguard patient safety, the guidance recommends sponsors streamline logistics and data collection, so they can rapidly assess new data in real-time and disseminate these data to investigators, IRBs and regulators.

	Overall, sponsors must weigh the benefits of an expanded cohort trial, including earlier access for patients, faster time to market and a competitive advantage, with its risks, including the uncertainty of a therapy’s safety and efficacy profile.

How to Contain Risk in Using Multiple Expansion Cohorts

	To increase the probability that an expanded cohort trial will proceed safely, the FDA’s Draft guidance recommends that sponsors concentrate on four strategies:

1) Monitoring and reporting safety issues

	As described in the Code of Federal Regulations, (CFR)

 sponsors are to ensure proper monitoring of its sites, and investigations are to be conducted in accordance with the general investigational plan and protocols spelled out in the IND application. Given the complexity of expanded cohort trials, and to be in compliance with this guideline, sponsors must make a concerted effort to select medical monitors who are trained and experienced in cancer treatment and clinical trial conduct to mitigate patient risk.

	To handle serious safety issues, the CFR, as well as the Draft Guidance, spell out how sponsors are to rapidly communicate these events to clinical investigators and regulatory authorities. Furthermore, the Draft Guidance states that there should be plans for activating protocol amendments to address the safety issues.

2) Establishing an independent safety assessment committee (ISAC) or an independent data monitoring committee (IDMC)

	The plan for management of serious safety issues should include an ISAC or an IDMC. These committees should be established for every FIH expanded multiple expansion cohort protocol, would be responsible for analyzing expedited safety reports, reviewing all serious adverse events, developing progressive summaries of adverse events, and recommending protocol modifications to reduce risks to the patients enrolled in the trial.

	The ISAC/IDMC, which is responsible for assessing the safety and futility of each cohort, can make suggestions for protocol modifications, such as:

	· Revisions to eligibility criteria for subgroups if the therapy appears to expose patients to greater risk

	· Changing the drug dosage or administration schedule to reduce the incidence of adverse events

	· Identifying emerging risks that must be communicated to current and future trial participants via changes in the informed consent form

	Even after initial approval of a clinical trial protocol, the trial remains subject to continuing review by an IRB throughout the trial. The sponsor must provide cumulative safety information to the IRB along with any other information it requires. Because of greater complexity and risk to patients, the FDA expects sponsors to assess safety on a periodic basis, typically more than once a year, on a schedule confirmed with the FDA. The FDA requires that sponsors keep investigators informed of emerging data on the investigational agent, especially data concerning safety and adverse events. The investigator, then, is expected to report this information as part of their continuing review to the IRB.

	To account for increased risks, IRBs should consider additional ad hoc meetings to review emerging safety data.  Alternatively, the FDA presents another option that institutes a separate IRB that can meet on short notice to review fresh data or revisions to FIH expansion cohort trials. Finally, the FDA recommends that sponsors use an experienced central IRB, as permitted, to expedite the review of multicenter FIH multiple expansion cohort trials.

4) Regularly updating informed consent documents

	During the course of the trial, informed consent documents must be updated to reflect new risks or protocol revisions that may affect a patient’s decision about participation or remaining on the trial. As FIH multiple expansion cohort trials are amended, the revisions, along with updates to the informed consent documents, should be submitted to the IND before they are implemented. Finally, to ensure the informed consent documents allow the patients to make an educated decision about trial participation, the FDA may request that the sponsor submit the original and all updated informed consent forms to the IND.

Multiple Expansion Cohort Trials Expedite Clinical Research

	Multiple expansion cohort trials offer a streamlined, efficient approach to drug development that sponsors can use effectively to develop the next generation of targeted and immune therapies for cancer and other diseases. As long as a sponsor understands and accounts for the known risks of this type of trial, multiple expanded cohort trials have the potential to make clinical development more efficient, enabling greater adherence to timelines and budgets, and speeding urgently-needed treatments to patients.

Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance for Industry. Draft Guidance. Food and Drug Administration. August 2018. Available at: 

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM616325.pdf

Clinical Research. Food and Drug Administration. January 2018. Available at: 

https://www.fda.gov/forpatients/approvals/drugs/ucm405622.htm

Getz K. Study Accessing Practices and Inefficiencies Associated with Site Selection, Study Study Up and Site Activation. Tufts Center for the Study of Drug Development. 2016. Available at: 

https://www.gobalto.com/research-report-tufts-2016

Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. Food and Drug Administration. 2018. Available at: 

https://www.fda.gov/ForPatients/Approvals/Fast/default.htm

McConnell I, Mulhearn C, Romanelli J, Holko J. Merck Receives Accelerated Approval of KEYTRUDA® (pembrolizumab), the First FDA-Approved Anti-PD-1 Therapy. Merck. September 4, 2014. Available at: 

https://www.mrknewsroom.com/news-release/prescription-medicine-news/merck-receives-accelerated-approval-keytruda-pembrolizumab-f

Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001) (KEYNOTE-001). ClinicalTrials.gov. ClinicalTrials.gov Identifier: NCT01295827. February 15, 2011. Available at: https://clinicaltrials.gov/ct2/show/NCT01295827.

Broderick JM. Keytruda Approved for Lung Cancer. CURE. 2015. Available at: 

https://www.curetoday.com/articles/keytruda-approved-for-lung-cancer

Barata P, Hobbs B, Rini B, Paller C, et al. A100 / 100 - Seamless phase I/II clinical trials in oncology: retrospective analysis of the last 7 years. Abstract. 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Available at: 

http://mct.aacrjournals.org/content/17/1_Supplement/A100

Number of Seamless Clinical Trials in Oncology Has Risen Recently. Press Release. 2017. Available at: 

http://www.eortc.org/app/uploads/2017/10/seamless_clinical_trials.pdf

Bugano DDG, Hess KR, Jardim DLF, Zer A, et al. Use of expansion cohorts in phase 1 trials and probability of success in phase 2 for 381 anticancer drugs. Clin Cancer Res. 2017. Available at: 

http://clincancerres.aacrjournals.org/content/clincanres/early/2017/04/04/1078-0432.CCR-16-2354.full.pdf

General Responsibilities of Sponsors. Code of Federal Regulations 21 CFR 312.50. Available at: 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.50

FDA. Code of Federal Regulations Title 21. 2018. Available at: 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32

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The rapid rise of targeted drugs and biologics in oncology has spurred sponsors and the FDA to innovate, leading to the creation of a variation to the typical trial design that can include multiple expansion cohorts.

Andrew Kinley, Ph.D.

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