Clinical News Roundup: Biopharm Seeks More FDA Input On Endpoints

By Ed Miseta, Chief Editor, Clinical Leader

Biopharmaceutical companies such as Novartis and GSK are seeking additional clarification from FDA on draft guidance on multiple endpoints in clinical trials.

In January FDA issued a 54-page draft guidance for sponsors and review staff outlining the agency’s thinking on problems posed by multiple endpoints in the analysis and interpretation of study results and how these problems can be managed in clinical trials for drugs and biologics. “As the number of endpoints analyzed in a single trial increases, the likelihood of making false conclusions about a drug’s effects with respect to one or more of those endpoints becomes a concern if there is not appropriate adjustment for multiplicity,” FDA says. “The purpose of this guidance is to describe various strategies for grouping and ordering endpoints for analysis and applying some well-recognized statistical methods for managing multiplicity within a study in order to control the chance of making erroneous conclusions about a drug’s effects.”

The guidance also addresses the three families of endpoints – primary, secondary and exploratory – and cases when companies go back and try to find a positive result from a failed study.

However, industry group BIO notes the draft fails to address several points worthy of attention, including multiplicity adjustments at the interim analysis and safety endpoints when assessing safety signals. BIO notes it would be helpful if the guidance provided some information about the criteria used to decide which methods to include.

Novartis says the draft guidance’s distinction between secondary and exploratory endpoints “remains unclear” and the company suggests that FDA elaborate more on this distinction by considering, for example, clinical importance and regulatory actions like additional labeling claims or descriptive statements in a package insert. Regeneron calls on FDA to draft separate guidance on multiplicity issues with safety evaluations of controlled trials, while GSK asked if FDA could provide “further discussion about the issue of multiplicity in studies not intended to demonstrate effectiveness and support drug approval and some of the methods that are more applicable for these studies (i.e. multivariate inferential methods, Bayesian methods, etc.).”

NIH Accelerates Multisite Clinical Trials

Developing new treatments for diseases often requires large numbers of clinical research participants enrolled in the same study at numerous geographical sites. These multisite clinical trials are well-positioned to discover whether a promising therapeutic is safe and effective, and may provide medical professionals with the information needed for treating their patients. However, the initiation of such studies may be delayed because each site typically relies on its own Institutional Review Boards (IRBs) to provide ethics reviews of the risks and benefits of the proposed research.

The National Institutes of Health (NIH) is leading policy and programmatic initiatives to streamline this overly cumbersome process. NIH’s National Center for Advancing Translational Sciences (NCATS) announced today that all Clinical and Translational Science Awards (CTSA) Program sites have signed on to the NCATS Streamlined, Multisite, Accelerated Resources for Trials (SMART) IRB authorization agreement. This agreement — which now includes a total of more than 150 top medical research institutions — will enable all participating study sites to rely on the ethics review of one IRB for each study, making it possible to initiate multisite studies within weeks instead of months. For patients waiting to enroll in a study, this could make a life-saving difference.

The SMART IRB authorization agreement serves as a model to help investigators adhere to the NIH’s policy on single IRB use for multisite studies. This policy was designed to improve IRB efficiencies while ensuring the protection of research participants so that research can proceed expeditiously.

The authorization agreement effort was led by Harvard Catalyst, University of Wisconsin-Madison Institute for Clinical and Translational Research, and Dartmouth Synergy. Through these institutions, a team of NCATS-supported SMART IRB ambassadors facilitated and provided critical guidance and support to assist institutions in joining and implementing the SMART IRB authorization agreement.

UK’s MHRA Details Issues In Clinical Trial Applications

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) on Wednesday issued guidance detailing the most common issues it sees in clinical trial applications in an effort to help sponsors avoid unnecessary delays. According to the agency, more than half of the approximately 1,000 clinical trial applications submitted each year require additional information before they can be reviewed and approved.

While MHRA typically reviews clinical trial applications for Phase I studies in around 12 days, and 22 days for other trials, the agency says that review times can double or triple when it needs to get more information from a sponsor. The agency notes when GNA points are raised, it can add up to 21 days to the final approval time for a Phase I application and 23 days for other phases, depending on the time taken for the applicant to submit their response and MHRA assessment of that response.

MHRA says that even with these delays, it is usually able to hold to the 60-day statutory limit for reviewing clinical trial applications, but acknowledges that the delays have negative impacts on both sponsors and patients.

The guidance itself is broken up into five separate documents detailing the top issues related to application validation: non-clinical and clinical data, information about the product itself and a list of resources with links to relevant guidance and standards for each of the aforementioned areas.

Patient Groups: Pharma Must Do Better

For recruitment rates in clinical trials to increase, the reputation of pharma in the eyes of patients will likely need to improve. Unfortunately, if the results of a recent survey are correct, that reputation may be getting worse.

The latest PatientView survey of patient groups shows a decline for pharma companies across many metrics. In 2016, just 37.9 percent of almost 1,500 respondents thought that the industry had an "excellent" or "good" corporate reputation. This was down from 44.7 percent in 2015, which was a peak for the industry since PatientView started conducting the survey in 2011.

There was also sobering news on the effectiveness of pharma's relationships with patient groups – a new metric added to the 2016 survey – with respondents sending a "must do better" message to the industry. There were declines for the industry across the board. Last year 74 percent of respondents felt pharma was either "excellent or good" at making high-quality products, but that declined to 64 percent in 2016. Being innovative still scored fairly well but slid 10 points to 59 percent, and there were similar trends for access to clinical trials and ethical marketing, which fell 27 percent and 25 percent respectively.

The survey also found that patient groups now think just 20 percent of drug makers do well on transparency. High profile pricing scandals also seem to have had an impact on patient perceptions. Just 11 percent of respondents felt the sector was doing a good job of providing fair pricing for its products, down from 15 percent a year earlier.

Overall, only 23 percent of patient groups thought pharma's corporate reputation had improved over the previous five years, whereas 28 percent had that opinion in 2015. And the industry is not alone, with almost all other groups covered in the survey (including generic and biotech firms) also seeing declines.

A Model For Safer & Cheaper Clinical Trials

Clinical trials are expensive and can be risky to patients. Reducing the cost and risk of these trials has been the dream of Amin Khademi, an assistant professor of industrial engineering at Clemson University. He now hopes to use mathematics to accomplish that dream.

Thanks to a $500,000, five-year grant from the National Science Foundation, Khademi hopes to find an algorithm that uses an adaptive approach to make trials safer and less costly. The approach looks at design and allocation. “Let’s say I am going to assign 20 of 100 patients to a very toxic drug. They’re going to suffer from a lot of side effects and may die,” he said. “Therefore, this policy to allocate patients equally is not the best approach.”

So if researchers are looking at four drugs, and they see that drug number 3 has the most potential and drug number 4 is the most toxic, using the new algorithm they could reassign patients — the most to drug 3 and the fewest to drug 4, for example — but still end up with reliable results.

“We’re proposing an adaptive approach, which is more ethical because you’re potentially not giving bad treatment to a lot of patients,” Khademi said. “As we are seeing a response, we change allocation in these groups and assign more patients to the treatment that is actually good. So we can prove which is best using fewer people taking potentially dangerous drugs.”

The research involves a technique called stochastic dynamic programming — a kind of math that can determine which slot machines to play to maximize winnings, for example. The same principles apply to trials, which involve random unknown factors. With differences in patient characteristics, finding the best allocation route can be difficult.

The plan is to use stochastic dynamic programming to devise software that can take into account all the variables and generate a model for researchers to get the same data with fewer patients by allowing them to adapt as data are garnered during trials. As the study progresses, researchers could put new groups of patients into treatments that are working instead of subjecting them to ineffective or potentially harmful treatments. Doing could potentially save lives and reduce the cost and duration of the study.