The shifting sands of the Phase IIIB-IV research industry

Merck's prescription painkiller Vioxx was pulled from the market five years after it first came on sale after a series of post-approval (Phase IIIB-IV) studies raised cardiovascular safety concerns.

Millions of patients worldwide had been taking the drug and the resulting backlash resonated throughout the pharma industry and left patients and doctors calling for more information to be made available on the risks and benefits of prescription drugs.

In response, the US Food and Drug Administration (FDA) has tightened its regulatory controls to make drug companies more accountable for transparency of its clinical trial data.

All drug study data gathered throughout the world by pharma companies, be it positive or negative, can now be subpoenaed by the FDA if they choose to probe deeper into a drug's clinical trial activity.

This has created a new sensitivity within drug companies and has led them to increase their clinical trial quality processes dramatically, Dr Hugo Stephenson, president of >Quintiles​ Strategic Research Services, told www.Outsourcing-Pharma.com.​

Before the issue with Vioxx, the $2.4 bn (€2 bn) outsourced Phase IIIB-IV clinical research market was split by a third between three main groups.

The first group is made up of academic research organisations (AROs), where the research is "investigator initiated" by a key opinion leader (KOL) in a particular field, who approaches a drug company for funding to run further trials on one of its existing drugs.

The benefit for drug companies engaging in this type of research is that by paying KOLs to perform the trials, they are effectively giving money to people who may otherwise be their biggest critics.

"By attaching their name to a trial these KOLs provide endorsement of the research, offering added credibility and creating "noise value" that will make people sit up and take notice,"​ said Stephenson.

The downside in using AROs is that the drug sponsor doesn't have much control over the study protocol or timeline and the trials have a habit of dragging on.

"Often what starts out as a two-year study could quite feasibly turn out to take up to five years,"​ Stephenson said.

For drug companies who are conducting trials where time is particularly sensitive, the second group, consisting of large global CROs, is a pertinent choice.

These companies make their bread and butter designing and conducting trials for drug companies to suit their specific needs and are completed in a time and cost-effective manner. However, they do not offer the kudos of a KOL attachment.

The third group consists of smaller CROs (20-40 employees) that are scattered throughout the world, often specialising in niche areas.

These companies were typically used by the marketing department in global branches of a large drug company to run post-marketing studies of a drug that are very return on investment (ROI) focused and specific to the local market.

Traditionally these companies were sourced from the local area where the trial was being conducted and were very flexible and price sensitive in design, but often lighter on standard operating procedures (SOP) and quality control processes, Stephenson said.

However, as the climate post-Vioxx poses the ever impending threat of being audited, big drug companies are now more wary of the nature of the trials they conduct, who in the company can initiate them, and what organisations they trust to conduct them.

This is because when a drug's trials are audited by the FDA, the sponsoring drug company is entirely responsible for ensuring all the appropriate quality control and SOP processes were followed during all the studies, even if they were outsourced.

Because so many money-spinning drugs are now sold under the same brand globally, results of a negative localised trial conducted in Germany, for example, could have resonating implications for the brand worldwide and this threat is becoming too much for drug companies to risk.

To regain control, big pharma headquarters have been pulling back on the budget and authority that its global branches have to conduct localised Phase IIIB and IV research outside the global jurisdiction.

In doing so have effectively been pulling back from smaller, local CROs, who were the prime recipients of these types of studies.

As a result, in the 18 months post Vioxx small CROs have been feeling the pressure, with the sector experiencing a period of consolidation, shrinking 10 per cent each year through a number of ongoing mergers and acquisitions and some companies going bust.

Academia and big CRO companies are stepping into their space, with their slice of the pie growing at a rate of 25-30 per cent each year.

"Quintiles is performing particularly strongly. As the leading provider of Phase IIIB and IV research we are growing above academia and as a result we are expanding our project managers in this area across the world,"​ said Stephenson.

"Our company has a special focus on Phase IIIB-IV, with 20 per cent of the business dedicated to this area. We are particularly strong in safety megatrials, the largest we conducted had 60,000 patients,"​ he said.

The next few years should see the market share of outsourced Phase IIIB-IV research move from an even three way split, to 40:40:20, as small CROs continue to lose ground.