Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Transparency in Clinical Trials

Curator: Larry H. Bernstein, MD, FCAP

Does Pharma Really Want Transparency In Clinical Trials?

Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @outsourcedpharm
http://www.clinicalleader.com/doc/does-pharma-really-want-transparency-in-clinical-trials-0001

My recent article on transparency in clinical trials, featuring Dr. Brad Thompson, CEO of Oncolytics, solicited a good number of comments and emails from readers. While most readers agree that more transparency would be good for patients and the industry, there seems to be a lot of disagreement over how it can be achieved, and if it can actually be achieved at all.

To recap, Thompson believes we still have a long way to go, and questioned whether true transparency would ever be achieved. His primary argument noted researchers who want to be published will not put much focus on neutral or negative trials, and even the press releases put out by sponsors include a limited amount of information.

One reader that works for a CRO made the following comment: “Dr. Thompson from Oncolytics made some very interesting comments about investigators holding back information. An investigator will enter patient data into an EDC system that is then verified by monitors. And that is just one of a number of sites. These investigators will generally know when a drug is working and when it is not. As a CRO, I often saw statistical outputs on blinded studies where you could see where the data was trending. Even data guys can tell if a drug is working by the data results and improvements in patients.”

If physicians and researchers are able to see clear results even when the data is still in the process of being collected, then what is the problem with being more transparent? One possible explanation is that once physicians know a drug will not work, they will no longer continue to place patients at risk by having them participate in the trial. This could be done for purely ethical reasons.

But there may also be reluctance to greater transparency on the part of the pharma company. “No drug company truly wants transparency because it leaves the results and outcomes more open to interpretation, mainly by Kaiser, Blue Cross and other groups,” noted another reader.  “Pharma companies could cost themselves a lot of money in sales if they do not have the time to target and position.”

Investors Are A Consideration

There is still another consideration at play. If a study is not going well, would it be to the benefit of the executives of a company to share those results? Let’s play devil’s advocate for a moment and assume you are the CEO of a biotech company. You’re making $500,000 a year with good benefits. You have several investors who have dumped millions of dollars into your company and your product. The study is targeted for four years, but within the first year you see results that indicate your drug is not going to produce the intended results.

“In that scenario, how prone would you be to ending the trial, saving the investors their remaining money, and losing your job?” notes one reader. “Are companies prone or pressured to locate new targets for therapy or identifying reasons to extend the trials, sometimes for a few years or longer?”

All of us have heard discussions about the possibility of electronic medical records (EMRs) someday replacing electronic data capture (EDC). According to one email I received, this will never happen because of the physician issue mentioned above. After all, if patient results were posted in the EMR and every doctor on the network has access to the information, everyone would know if I drug was not having the desired effect. As soon as that happens, promises of riches being delivered to investors will fall by the wayside, and executives will be out of jobs.

“Within big pharma, this is called job preservation,” noted another reader. “If funding for the trial is cut, I am out of a job. At the same time, trial results are not getting any better for patients. Years ago about one in three trials resulted in a successful outcome. Then it went to one in four. Today that success rate is around 15 percent with R&D commitment at about 12% (down from approximately 28%). It appears that the industry is run by money and managed by guys who know how to play the system.  If patients are the primary concern, the industry would target physicians who have the right patients, get enrollment done faster, and quickly identify if the product works as advertised.”

Limit Procedures And Additional Fields

Going back to Thompson’s comments, the problem is not always investigators wanting to get published. One reader noted oftentimes it is the in-house pharma and biotech doctors as well as researchers in academia who are anxious to get their names into publications. “Unfortunately, these are often the same people who include numerous unnecessary procedures in protocols. They will also ask for additional data fields to be included in EDC systems after study launch, which can delay database activity for two months. The reason is they see a hint of something and decide they want to dig deeper, even if the activity has nothing to do with the study results and the overall goal of the trial.”

The obvious fix to this would be executive leadership and study teams standing up and challenging the reason for inclusion of the additional data fields, which cost the industry both time and money. A large number of procedures should be challenged as well, especially if they are not standard of care.

“If a researcher sees a hint of something that seems to be interesting but has nothing to do with the study, they should engage one of the thought leaders to conduct an IIR program to see if the hypothesis is valid,” notes the reader. “They can do this while keeping the clinical program on track to closure without delay, and still appease their interests.”

Clearly, there are no easy solutions. Many pharma companies are certainly making a concerted effort to put the patient first, and I believe those efforts are sincere. But there is no question they must also be focused on funding and trial results – the industry has gone from one focused on a patient to one driven by investors, and that trend is unfortunate. Physicians and researchers will always have their own goals and aspirations, and placing additional burdens upon them could have the unintended consequence of driving them away from trial participation – poor sponsor/CRO pay practices and poorly written/detailed protocols have already moved many physician practices away from clinical trial participation. Coming up with a solution will likely involve bringing together all stakeholders for a more in-depth discussion on the topic, which unfortunately I don’t see happening anytime soon.

Transparency In Clinical Trials: Will It Ever Be Achieved?
Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @outsourcedpharm

A lot has been made recently about transparency in clinical trials. In the EU a new regulation is about to address the issue, and CISCRPrecently sent a petition letter to the FDA asking it to pass a similar regulation in this country. The petition, signed by hundreds of patients, hopes to make trials results more accessible to patients.

It’s also not hard to understand why a patient participating in a trial would want to know the results of the study, and whether or not they received the active drug or a placebo. But while changes might help companies with patient recruitment and retention issues, will true trial transparency ever be possible?

Dr. Brad Thompson, CEO of biotech firm Oncolytics, believes we still have a very long way to go, and that perhaps pharma companies are not the ones that should be blamed. “I think a lot of people, patients especially, believe that companies are the roadblock in keeping the results of clinical studies from becoming public,” he says. “But personally, I believe it is a much wider issue than that, especially when it comes to finding out the results of unsuccessful trials.”

For example, Thompson looks at clinical investigators. He notes many of these individuals would like for their academic careers to progress. For these folks, the reporting of trial results, especially those that are negative or neutral, does nothing to advance their goals. It is not a deliberate action to conceal information, but the lack of an incentive to do so can often result in delays, provided the results are reported at all.

“If you are conducting a trial at 50 or 60 locations, it doesn’t take too many of them not reporting information to significantly slow down the ability of a sponsor to report on what is going on with the study,” notes Thompson. “And the more time that goes by, the more people will lose interest in doing so. Add to that the fact that there are no journals or annual meetings that are focused on reporting negative results. This is due to space and time limitations. If there are 100 speaking opportunities at the ASCO show in June, those spots will be given to people reporting exciting new results in cancer therapies. There is no time for, nor interest in, anyone reporting on therapies that didn’t work.”

From the standpoint of a public sponsor company, they will typically report negative trial results, but that will generally be via a press release, where there is very little detail. It’s also unlikely that a patient participating in a trial will be on the company’s PR distribution list. As a result, there is an entire system set up with no positive incentives to go into more detail about trials that did not go as planned.  That in itself is unfortunate, since we often learn as much from things that don’t work as we do from things that do.

“In many ways, knowing what didn’t work, or what caused a safety problem, can be more important than knowing what did work and knowing there were no safety problems,” adds Thompson. “Knowing of negative results will allow you to improve your own trials and continue to work to try and find something that does work. I think this is a bigger issue than people realize and it is not something that will be easy to address.”

All Requirements Fall On Sponsors

Of course in this entire daisy-chain of events, there is only one party involved that has a legal obligation to disclose positive or negative information on the trial. That is the sponsor company, which by law is required to disclose information about the trial. Failure to report something could result in a criminal offense. If an investigator doesn’t disclose something, they do not face the same negative repercussions.

“If you talk to an attorney from any sponsor company, they will tell you how important it is to disclose, disclose, disclose,” says Thompson. “They fully understand the importance of doing that. The situation might be slightly different in privately-held companies, because public companies have an obligation to their investors. But even then they have a duty of disclosure under the investment terms. More often than not the investors are sitting on your board of directors and would be privy to the information anyway.”

On a positive note, Thompson is quick to note that most companies, investigators, and researchers he knows want to disclose as much as they possibly can.  There are just a number of soft reasons that might end up keeping them from getting into more detail than they do. For example, there is generally the same amount of content going into a press release regardless of whether or not the trial was successful. He notes no one on the planet is going to put out a 30-page press release covering the detail of a clinical study, whether it was good or bad.

For that reason, most of the press releases that go out are seldom more than two pages, with just a few sentences on the results and the safety aspects. While that will meet the disclosure standards, it certainly does not disclose much detail to the investigators or others who wish to know the details.

“When you look closely at this situation, what you see is a system that is almost accidentally set up to inhibit full disclosure,” states Thompson. “The industry might feel it is good to publish negative results, but where would we publish them? Who is going to pay for it? Who is going to read it? It’s a difficult issue. You can try to induce people to do things, but if an investigator has a failed study, his academic career will not be helped by spending the weeks it would take to write a paper to be published. Especially if they can spend that time writing a paper on a study that did work. There is not a conspiracy of silence. It is just natural for people to want to focus on things that will help them out with their careers.”

More Information Benefits Patients

There are other reasons for reporting as much information as possible. Patients appreciate the information, but from the sponsor perspective, more information might mean coming up with better versions of existing medicines. Thompson likes to use bone marrow studies as an example of how more information can be helpful to patients. When physicians first started using radiation to kill off bone marrow for certain types of leukemia patients, that marrow had to be replaced. It was discovered that bone marrow transferred from people who did not match the patient’s tissue type caused them to perform better…but only for a period of time. After that, the patients began to die quicker. Still, researches published the complete findings.

“They could have reported that non-matching bone marrow works really well for six months and left it at that,” says Thompson. “But they opted to include the downside of the study as well. That led physicians to decide it would be used for emergency use only until a better match could be found. That knowledge ended up making these transplants better for the patients and better for the industry. I think in that case we were lucky that there was a positive effect to report along with the negative. If there was only the negative effect, I don’t know that it would have ever been published.”

Is There A Fix?

I wish I could report that there is an easy fix to this transparency issue. Unfortunately, there is not. According to Thompson, there are not a couple of adjustments that can be made to correct the problem.  After all, you cannot force a researcher to publish an article on a failed study if they have more important needs to attend to. You can’t force a company to produce or publish a 30-page press release or, if they did, force anyone to read it. Unfortunately, that is a reality of the industry.

“We need to come up with a mechanism where the end result is of benefit to the industry, such as people having access to needed information and disseminating it without the process being burdensome,” notes Thompson. “I honestly don’t know how you do that.”

There are so many pieces to this problem…the sponsor companies, the FDA, the investigators, the research sites. It is difficult to fix a problem when the players involved in it are so varied. Still, if this is an issue that is too complicated to tackle with all players at once, perhaps the best approach would be to take it one step at a time. If we put sponsors, patients, and investigators in a room together, all would likely be clamoring for the same end result.

“We would not see pockets of stakeholders fighting this,” adds Thompson. “A solution to this transparency problem would make everyone better off. It’s frustrating because everyone knows this is an issue, and that we have to do better. People who are a lot smarter than I am have spent time on this and were not able to come up with an answer.  But the fact that this is a complicated issue doesn’t mean we should throw our hands in the air and give up. Eventually we will have to produce a solution.”

Taking The “Risk” Out Of Risk-Based Monitoring

http://www.clinicalleader.com/doc/taking-the-risk-out-of-risk-based-monitoring-0002

The clinical trial landscape is continually evolving and with it, efforts in the improvement of participant safety and data integrity. CROs are beginning to transition from on-site monitoring, with 100% point-to-point source data verification, toward a risk-based monitoring (RBM) approach that utilizes source data review and more centralized monitoring techniques better adapted for mitigating risk.

While RBM has gained considerable attention in recent years, reluctance still remains around the approach—from uncertainty arising from the use of “risk” employed in its name to sponsors being wary of potential implications on data quality and regulatory inspection outcomes.

Despite these concerns, there is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% source data verification to ensure subject protection, data integrity, and overall study quality.

Improve the Inclusion & Exclusion Criteria for Your Next Clinical Trial

http://www.clinicalleader.com/doc/improve-the-inclusion-exclusion-criteria-for-your-next-clinical-trial-0001