Clinical Trial Complexity, Diversity, And Right To Try Continue To Impact Pharma

By Ed Miseta, Chief Editor, Clinical Leader

If it’s the first quarter of a new year, chances are that Michael Martorelli and his research team at Fairmount Partners has been hard at work preparing their annual questions issue of the Pharmaceutical Outsourcing Monitor. With the latest issue addressing 16 questions addressing pharma and biopharma companies for 2016, he once again does not disappoint readers.  

The first question addressed in the report relates to mergers and acquisitions. The industry has certainly seen its share of this activity in recent years. In just the last several months, acquisitions have provided needed services to companies such as BioClinica (MediciGroup and Synowledge), Capsugel (Xcellence and Powdersize), ICON plc (PMG Research), and WuXi Pharm Tech (Ambrx). Martorelli does not expect this acquisition activity to diminish in 2016, and expects combination activity to actually increase.

Are Trials Becoming More Complex?

One question I heard asked many times in 2015 related to the complexity of Phase 3 clinical trials. But are these trials actually becoming more complex? Researchers have also attempted to answer that question, sometimes with differing results. The Tufts University Center for the Study of Drug Development (CSDD) has conducted research showing that Phase 3 trials have, in fact, seen an increase in complexity. The groups’ analysis of 10,000 protocols conducted by drug development companies (contained in the datasets Medidata Solutions) shows the typical clinical trial now contains more endpoints, procedures, eligibility criteria, CRF pages, protocol amendments, and investigator sites than trials conducted just 10 years ago.

However, the Outsourcing Monitor also cites a study conducted by the University of the Sciences that examined data from www.clinicaltrials.gov. The report concluded that “…there is limited evidence for significant increases in the study and protocol design and execution of Phase 3 clinical trials sponsored by pharmaceutical companies.” Which raises the question of whether Phase 3 trials are really more complex, and if so, why the discrepancy between the two studies?

 Martorelli gives three possible explanations. The first is that measuring complexity may not be as easy as it might seem. He notes that many in the industry have already expressed that the clinicaltrials.gov database is not nearly as comprehensive as the designers intended it to be. Finally, analysis of data from all sources, including large and small pharma and biotech companies, as well as government and academia, may obscure differences that might be more apparent f the data were evaluated in studies of separate segments of organizations.

Furthermore, if researchers are looking at data that was provided voluntarily and not in a timely manner, that can also lead to problems. While the answer to this question might be ambiguous at the current time, my gut reaction, based on interviews I have had with clinical executives at shows and conferences, is that Ken Getz and his team at Tufts are on the right track.

Diversity Remains A Problem In Trials

There are a lot of problems that pharma needs to address with clinical trials. Bringing down the time and cost of conducting them, getting more patients on board, and making them more user friendly for the patients who are on board are just a few. But the problem of minority enrollment in trials is another one that does not seem to go away. A recent story on NPR’s morning edition noted that while 40% of Americans identified with a racial or ethnic minority group, very few are present in clinical trials.

The problems that can occur with this underrepresentation have the potential to affect the health of users post-commercialization. Martorelli notes a couple, which appeared in an article in PLOS Medicine:

• Black Americans on Bidil (isosorbide dinatrate/hydralazine hydrochloride) for the treatment of heart failure show a lower mortality rate than whites.
• Blacks whose ancestors come from different regions of Africa have different risk variants for kidney disease
• Pacific Islanders are generally not able to convert the antiplatelet drug clopidogrel into its active form.

While the Revitalization Act of 1993 attempted to remedy the situation by requiring all federally funded clinical research to make the inclusion of men and women a priority, the underrepresentation is still a problem. Pharma and its partners can only do so much to try and reach patients of every race and ethnicity. While new tools from the FDA will help companies to track the participation of patients in minority groups, a solution for pharma does not appear to be on the horizon.

Right To Try: Good Or Bad For Drug Development?

Right To Try is a hot topic in the industry and one that will result in emotionally charged discussions, regardless of which side you are on. A recent book and an article in the American Medical Association Journal of Ethics have brought renewed visibility to the subject. Both bring up interesting points that the industry will need to address regarding expanded patient use of investigational drugs.

The primary issue comes down to this: If the FDA approves the request and the manufacturer agrees to supply it at a minimal cost, what will happen, and who will be responsible, if an adverse event occurs? Additionally, what will happen to the status of any clinical trials that were ongoing at the time of the adverse event?

While the compassionate feelings we might all get when considering patients who are suffering, and what effect a new medicine might have on their condition should be considered, Martorelli concludes, partly from a personal experience with a family member, that circumventing the normal clinical trial process to hope for a solution that is at best a long shot, is likely not good for the patient nor the industry, and could end up doing more harm than good.

What’s The Status Of EU 536/2014?

One final question I would like to address concerns the European Regulation 536/2014, which was published in June 2014. The regulation was passed to correct deficiencies contained in Directive 2001/20/EC (implemented to simplify and harmonize provisions governing clinical trials across the EU) and makes the EU a place where it is easier for companies to conduct clinical trials. After implementing the directive in 2014, problems arose, including a doubling of staffing requirements, increases in insurance fees for sponsors, a doubling of administrative costs, and an increase in trial launch delays of 90 percent. These problems caused the number of trial applications in the EU to drop by 25 percent between 2007 and 2011. Although there has since been a recovery, Martorelli notes the EU is still not seen as the easiest place for a sponsor to start a multi-country trial.

Part I of the new regulation deals with territory-wide provisions for initiating a trial and reporting results while Part II deals with country-specific authorizations concerning trial subjects. The regulation is considered a major overhaul of the authorization and oversight process, and is expected to streamline the application process, create an operational database for new trials, and specify a single set of supporting documents to begin a multi-country trial.

Regulation 536/2014 is now expected to go into effect by October 2018, two years later than originally planned.            

Martorelli tackles other topics as well, including industry profit margins, CROs becoming technology companies, M&A activity in 2016, and more. The January 26, 2016 Pharmaceutical Outsourcing Monitor can be obtained by emailing Michael.martorelli@fairmountpartners.com or by calling 610-260-6232.