Urologist, former regulator shares FDA insights

Urologist Daniel Shames, MD, has had a unique and varied career, with stops in clinical practice, the FDA, and his current role as a consultant to the pharmaceutical industry. Dr. Shames’ wide-ranging experience brings an insightful perspective on the topics he discusses in this interview: what goes into FDA drug approvals, quality of life endpoints, and the Sunshine Act. The interview was conducted by Urology Times Editorial Consultant Philip M. Hanno, MD, MPH, professor of urology at the University of Pennsylvania, Philadelphia.

Please give a brief overview of the various roles you’ve had throughout your career.

After I finished my residency at the University of Pennsylvania, I entered service in the Army and then set up a clinical practice in Columbia, South Carolina, working with two other urologists. I did that for about 18 to 20 years and then decided I wanted to get out of clinical medicine and move back to the Northeast.

I applied for non-clinical positions and got a job at the FDA in 1996. My career at the FDA lasted 12 years. Six of these were spent as the director of the FDA’s Division of Reproductive and Urologic Products. Eventually, if you reach a certain level at the FDA, you are sought after as a consultant to the pharmaceutical industry or recruited to work for a pharmaceutical company. I left the FDA in 2008 to set up a consulting practice, where I currently work with most of the top 25 bio pharma companies as well as medium and start-up firms, helping them with clinical trial design and interactions with the FDA. Additionally, I perform due diligence for investors seeking to purchase a drug company or a particular drug, and consult with law firms regarding litigation that involves FDA drug issues. (Also see, “For this urologist, three careers have been gratifying")

You were far ahead of the curve as a medical officer in the FDA when you championed the use of quality of life indices and subjective results as primary and secondary outcomes in pharmaceutical trials. How did you engineer this change, and do you think this has turned out to be a good thing?

I think it became obvious to me that these changes needed to happen. This was a time when we were receiving a lot of submissions related to sexual dysfunction-both male and female-incontinence, and menopausal symptoms (the division regulated both urologic and gynecologic drugs), among others. We also had to deal with conditions such as interstitial cystitis and nocturia. For these conditions, merely counting episodes of intercourse, incontinence, or hot flushes etc. may not wholly support the benefit of a drug. In order to support the benefit of drugs of this type, one needs to know what the patient perceives as a clinical benefit. That’s how it became natural to me that we needed to become more active in terms of patient-reported quality of life.

At the same time, there was a movement in the FDA to go in that direction. I became part of the Patient-Reported Outcome (PRO) Committee, and ultimately guidance was developed on how to do these things. It’s become more important. At the time, we did have some meetings with the industry regarding these issues to get them stimulated in that direction.

What are the negatives of using quality of life endpoints as primary endpoints?

The main negative is that some diseases are very difficult to characterize in terms of drug efficacy as reflected in a PRO. Interstitial cystitis or irritable bowel syndrome (I was acting director of the GI division for about a year) is a good example. There are so many different domains and effects. Investigators have made lots of attempts and I know there have been some successes, but conditions such as these are quite difficult to quantitatively characterize. In addition, in order to get a drug approved using these measures, one should follow recommendations that can be found in the FDA’s PRO guidance, which can be found on their website. A published article that supports the “validity” of a PRO is usually insufficient to support use of that PRO in a clinical trial intended for drug approval.

In certain other areas, such as sexual dysfunction, there has been a lot of progress in developing some of these instruments. As you know, the mathematics of it is quite complicated; it mimics psychometric testing. Also, there’s another important additional question that arises; namely, even if we can measure a change, what is clinically meaningful? So there are additional processes to determine the clinically meaningful effect size. It’s a very complicated process, but for a lot of indications, I think it can be done successfully.

Do you think that the placebo effect is stronger when you are using subjective endpoints?

No. Even for objective measures like incontinence episodes or those used in erectile dysfunction trials, there is often a large placebo effect. A well-designed clinical trial incorporating a PRO instrument should not have a different placebo effect than one that used “objective” measurements.

You have seen the rise of direct-to-consumer advertising as a practicing urologist, as a government regulator, and as an industry consultant. What are your views on the benefits and the downsides?

Quite frankly, I think there can be an educational benefit to consumer advertising. A downside might be patients asking for drugs that they may not need, but generally I think direct-to-consumer advertising is a good idea. I also think it’s here to stay because of the need for both companies and patients to be able to communicate in some sense in the public arena. As always, physicians are the “learned intermediaries” in these processes when it comes to prescription drugs.

What does the FDA take into account when it decides whether to approve drugs? Is efficacy alone the requirement, or are there other factors?

The term the FDA uses is effectiveness. Effectiveness has to do with both the safety and the efficacy of the drug. The FDA makes a risk-benefit calculus, which is not clearly, totally quantifiable in most cases. There is some judgment there, and it can be very difficult. Even the usefulness of a drug-how easy it is to use-may be taken into account. There may be considerations about what else might be on the market, although technically in the United States, one does not evaluate comparative efficacy, but that may be in the back of reviewers’ minds.

Unfortunately, the U.S. public often doesn’t understand that just because a drug is approved by the FDA, that doesn’t mean it’s totally safe. No drug is totally safe. In fact, there are often significant risks, and both physicians and patients should take the decision to use a drug very seriously. As mentioned above, the concept that a drug requires a prescription written by a “learned intermediary” is different than drugs designed for over-the-counter use.

How does the FDA decide what is too much risk?

There is no clear-cut rule, but a lot has to do with indication. If the agency considers the indication life threatening, it will accept more risk. If it’s less life threatening or induces less morbidity or mortality, perhaps the FDA would accept less risk. For example, the FDA would likely accept less risk for a sexual dysfunction drug than it would for a cancer drug that might prolong life. That said, there are measures that can quantify these types of “quality of life” issues. As you know, some patients may perceive their sexual health as more important than a few weeks, months, etc. more of life. These are complicated topics.

When making a determination, does the FDA take into account how drugs will be used apart from the basis on which they are approved?

In general, a prescriber can use a drug for most anything once it is approved. The concern that a drug may be used off label may be in the back of the mind of reviewers when looking at drugs. I think that concern-whether a drug might be abused or used for a lesser or inappropriate indication-is considered to some degree, depending on the situation and in some when the concern is great, restrictions can be placed on the use of the drug as a condition of approval.

Can the FDA put together good advisory panels if all the experts are required to have no relations with pharma?

It is a challenge, and people at the FDA have complained about this issue. You have to either ask people who are not involved in trials or ask people who are involved in trials and have them disclose their financial arrangements. This limits the number of people who can sit on a committee. That said, this process is changing but is a continual challenge. I believe the FDA does the best it can under these circumstances. Usually, you can find enough qualified people to sit on a committee.

Do you think an industry consultant can serve as a primary investigator on the same drug he is a consultant for, or is this a conflict of interest?

I don’t think we will ever be able to eliminate that. The key is transparency. Years ago, there was no transparency. As long as everybody knows the relationships-especially financial relationships-then I think it’s probably OK and people can make their own judgments. My assumption is everybody has some biases; it’s just a matter of what are the bases of those biases: financial relationships, personal, professional relationships, long-maintained opinion on a particular topic, etc.

That’s a good segue into the next question. Originally adopted as part of the Affordable Care Act in March 2010, the Sunshine Act requires pharmaceutical companies and medical device makers to report annually to the Centers for Medicare & Medicaid Services about transfers of value they make to physicians and teaching hospitals. This information is then posted in a publicly accessible database. By 2015, more than 70% of drug sales will be in countries with such measures. Should physicians be concerned about this?

I don’t think so. It’s like email; I’ve always told co-workers not to put anything in an email that you wouldn’t want to appear on the front page of The Wall Street Journal. For most physicians, I don’t think a huge amount of money will appear on the database; this has more to do with academics, perhaps, and teaching hospitals. But I think if you are doing what’s reasonable and you feel comfortable about it, there shouldn’t be a problem. If some people are doing things that they don’t feel comfortable about and are going to be embarrassed by, then they need to rethink the financial relationship they have with the drug company.

Do you think some physicians may be less likely to participate in programs like pharma-sponsored educational events or collaborations because of the potential public backlash?

That’s up to the individual physician. I don’t see anything wrong or immoral about being compensated because you are an expert in the field. If you feel your compensation is reasonable, you should not be upset that it’s going to be publicly available. These days, almost everything is publicly available. As you probably know, a lot of this information was made available by private organizations several years ago, and I think you have to go about your life these days assuming there is very little that you can keep secret.

As firms already have data on each physician’s prescriptions, with the Sunshine Act, they will also have data on how much they and their competitors spend to market drugs to that physician, improving their control of marketing results tracked by expenditure on each physician. How is this likely to impact the behavior of pharmaceutical companies?

Drug companies may market to certain physicians or change their marketing behaviors, but ultimately, physicians have the control to decide what they want to prescribe perhaps within the confines of a formulary. Physicians should be educating themselves regarding use of pharmaceuticals. I don’t know how this is going to change physician behavior, but many entities-pharmaceutical companies, Google, Facebook, etc.-already know a huge amount about you not just as a physician, but as a person.

Over the last several months, large pharmaceutical companies have been in the news for questionable behavior. Johnson & Johnson settled state consumer fraud complaints about off-label marketing of Risperdal for more than $2.2 billion. Novartis has been accused of inducing pharmacies to switch thousands of kidney transplant patients to its immunosuppressant drug mycophenolic acid(Myfortic) in exchange for kickbacks disguised as rebates and discounts. In your unique position of having been a provider of care, a high-level FDA employee, and now a pharma consultant, can you shed any light on why this is happening? Is it a new development, and is there anything that can be done to curb this behavior?

I am not sure that it’s a new development. There have always been problems like this. First, let’s make it clear that what you see in the media is not always what really happens. You have to know the individual case. I don’t think it’s appropriate to make an opinion about a particular case unless you know the actual details.

Second, I don’t think the pharmaceutical industry is different than any other industry. It’s got people, and some of the people are not perfect, which is why we have regulations. Having worked for a regulatory agency, I am a believer that in certain areas, we need to have regulations.UT

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