Center for Drug Evaluation and Research

Index for 2001

• Tolerance and Openness
• The Art of Reading Tea Leaves
• Minutes Save Months
• To Err Is Human, To Admit It Sublime
• An Opportunity for the Taking
• Reserve Disdain for Supermarket Checkout
• Tolerance
• Annual Report: Process Problems, Unfairness Top Complaint List

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Tolerance and Openness

Tolerance, by definition, is the absence of bigotry or a civil and fair attitude towards those whose viewpoints differ from our own. But being tolerant doesn't require that we must reevaluate our views in light of a newly received opinion. We simply must treat others' views with civility and, at least superficially, respect.

Contrast tolerance with openness. Openness implies not only tolerance, but also a willingness to reassess our own views when confronted with a differing viewpoint. True openness requires that the reassessment be genuine and not forestalled by a superficial analysis of the qualifications of the espouser of the new opinion. True openness is a rare commodity.

We become experts in our field of drug regulation. We form opinions and make findings of fact, sometimes based on much training and study. But they are also based on fundamental assumptions about the world and on our personal value systems and experiences.

Understandably, we become very comfortable with our opinions and beliefs. Faced with ideas that are inconsistent with those opinions and beliefs, we resist.

The people we serve, the public, are a diverse population, and they don't necessarily share our experiences, training or values. They may come to different conclusions, given the same set of facts. Are they wrong? Is there an absolute right or wrong?

As I have often said, drug regulation is one of the most complex endeavors one can tackle. Part of good regulation is based on science. Rightfully, we value highly our scientific knowledge and insights into the pharmaceutical and clinical sciences and the law. But that is only a part of the story. A significant part of drug regulation involves societal issues, values and judgments that, even within CDER, may differ.

Every day, we makes decisions about what is best for the public health. Of necessity, these decisions are often made with less information than we would like, because if we waited for all the desired data, bodies would start to pile up. In part, these decisions are also based on values and assumptions that have little relevance to science.

How much should we rely on physicians and patients to read labeling? If they misuse drugs because of failing to read or understand labeling, does responsibility for the consequences, which may include deaths, fall on them or on us? What should trigger removal of a drug from the market? How does one balance the benefit of improved quality of life for some against serious damage caused to others? Is a longer life in pain better than a shorter one free from pain?

These are difficult questions. Ask various people, inside FDA or outside, and you will get a broad spectrum of answers. There are no magic formulas that can be relied on to make these decisions. There are no absolute truths. We cannot expect to be right all the time, whatever "right" means.

Given the uncertainties, it is vital that we articulate clearly the basis for our decisions. And we should view the inevitable criticisms of our recommendations and decisions as an opportunity to reevaluate our positions, to challenge our assumptions and to learn.

However, learning does not occur if our mindset is one of mere tolerance for differing viewpoints. Learning comes with genuine openness.

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The Art of Reading Tea Leaves

As I've noted many times, those outside CDER often view our new drug review process as a giant black box. In the absence of complete transparency, applicants sometimes look for occult signs and surrogate markers to tell them how their new drug applications are progressing.

Applicants who are not seasoned veterans at maneuvering NDAs through the review process sometimes interpret the statements from Center staff and Agency actions in a manner that is just about as accurate as reading tea leaves.

Lately it seems that I've been seeing more unsuccessful tea-leaf reading than usual. I thought it would be useful to those on both sides of the regulatory fence to share some examples I've encountered.

These examples all relate to firms that have come to me in a state of shock after they received not approvable letters. I've divided them into erroneous interpretations of statements made by CDER staff and false inferences based on activities by the Agency during the review process.

In meetings or telephone conversations with CDER reviewers and project managers, applicants may ask: "Do you need any more information?"

The reviewers may say: "No, we have all the data we need," or, "No, there are no outstanding issues." They mean that the application is complete—not necessarily approvable—and that no more amendments to the NDA are needed for them to reach a decision.

Unfortunately, some applicants think this means that there are no problems with the drug, the data or the application.

As a word of advice to reviewers and project managers, it would be good to emphasize to applicants that we won't know whether the application is approvable until all the data have been reviewed.

Another occasionally misunderstood statement is, "There are no issues that need to go to the advisory committee."

Some applicants take this to mean that the data are so good that the drug is clearly safe and effective. But it could also mean that the data are so negative that the drug is clearly unsafe or ineffective, so there is no reason to waste the advisory committee's time. Most often it means that the drug is not novel, and there are no real areas of uncertainty.

Sometimes applicants interpret the absence of contacts or questions to mean everything is fine with the application. "No news is good news" may apply when your teen-ager borrows the car, but it is useless in predicting the outcome of an NDA review.

I have heard applicants say, "But DSI [the Division of Scientific Investigations, which inspects clinical investigators] did their inspection, and everything seemed fine. They wouldn't have done the inspection if the application was not approvable." Wrong.

I've also heard the same thing said about field investigators inspecting the manufacturing facility for current good manufacturing practices.

Those assumptions may have had some validity years ago. However, with the short user-fee review timeframes in place today, inspections are ordered very early in the review process, before any conclusions can be made about whether the application is approvable.

Even if the reviewing division believes that an application will not be approvable, the inspections are done so all deficiencies can be identified and conveyed to the applicant.

The Center gets many applications from startup companies run by entrepreneurs who have invested years of sweat and a lot of their own money in the development of a single product that will make or break them. It is only natural that they are extremely anxious about the progress of their application. They seek any clue they can find about how their drug is faring.

With that in mind, it is important for us to be very careful to avoid inadvertently misleading applicants by being less than crystal clear about what our statements and activities mean with respect to the outcome of their applications.

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Minutes Save Months

I've often said that 90 percent of my work consists of picking up the pieces after breakdowns in communication. Ninety percent may well be too low an estimate. The most common scenario of miscommunication occurs when we are not crystal clear in what we say and the listener doesn't want to hear our message. Imagine you are the NDA applicant in the following example.

You work for a privately owned startup pharmaceutical company. It has purchased the rights to develop a new drug for the U.S. market from a company that went belly-up. The defunct company had completed Phase II studies, and the drug appeared promising.

You were hired to oversee the Phase III testing and to assure that the drug receives FDA approval. You have been working on the project for three years. You followed the guidance FDA gave you in the end of Phase II meeting, and your statisticians believe the data from Phase III trials demonstrate the drug is safe and effective.

You arrive with other members of your team in Rockville to attend the pre-NDA meeting. The CDER staff members at the meeting agree that the drug has great potential and that things look promising. However, they state:

"It would be advisable for your company to do an additional study to address questions raised by somewhat elevated liver enzymes in a small percent of the subjects in the studies."

When you ask if the study is a requirement for approval, the CDER participants say only: "It would be very helpful."

When you caucus with your team after the meeting, there is some uncertainty as to exactly what CDER said. Most of your team agrees that the Center meant that it would be OK to submit the NDA, and that the additional study could be done in Phase IV after approval. Your team estimates that it will take three years additional work to complete the suggested study. You think that there is a small chance that FDA would not approve the NDA without the additional study.

When you get back to your room in the hotel, there is a message from the CEO of your company asking how the meeting went. You see three possible scenarios of what to say in returning the CEO's call:

A. "Well, boss, we didn't do very well. We'll need to do another study, which will take another three years before we can submit the NDA. But there is a bright side. We can save the $50,000 you would have paid for my bonus. For that matter, you can save my salary for the next three years, too. And the bankruptcy judge will look favorably on any company that sacrifices itself to prevent even the possibility of its product doing harm. By the way, I'll be staying around here for a few days to look for a new job."

B. "Well, boss, we had the meeting, but we can't figure out what FDA said. I think we can file the NDA, but maybe we should first do this three-year study they suggested. What do you think?"

C. "Well, boss, the meeting went fine. We are on track to submit the NDA next month. They suggested an additional study, which I'm confident we can do in Phase IV."

Which of the above scenarios would you choose?

The point is, when so much is at stake, people will naturally interpret our statements to suit their expectations best. Therefore, it is essential that we be clear and precise in verbal statements and, most importantly, in the minutes of meetings.

Equally important is the timeliness with which minutes are conveyed to the company. CDER MaPP 4512.1 specifies that minutes of formal meetings be transmitted to industry participants within four weeks. Clearly stated minutes do little good if they are sent six months later, after the applicant has submitted an NDA or has begun studies according to misunderstood verbal guidance.

Not only must the firm receive the minutes in a timely manner (or check with the project manager if they have not been received in four weeks), but the firm should send their minutes to CDER, and we should read them.

I've heard some in CDER say: "Our minutes are the official ones, so we don't need to read the firm's version." That is technically true, but costly if the firm's minutes show a misunderstanding about a planned study, and no one catches it until the study has been completed and an application is submitted.

If there is a misperception, it is better corrected sooner than later. The added time it takes to review the firm's minutes is well worthwhile, even if only occasionally significant differences are detected.

Anyone who has sat through long meetings following appeals can attest that clear and timely minutes can save months of work on both sides of the regulatory fence.

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To Err Is Human, To Admit It Sublime

People who do not admit they made a mistake, particularly when the mistake is obvious to all around them, are sometimes likened to an ostrich burying its head in the sand.

Although ostriches lack some social graces, that characterization does them a disservice. When an ostrich appears to bury its head in the sand, it is actually putting its ear to the ground to better hear the approach of predators. That leaves humans who refuse to admit mistakes pretty much in a class by themselves.

It's bad enough when individuals do it, but when organizations refuse to admit mistakes, it infuriates those who are affected by the error. Remember the tobacco company executives with their right hands in the air, swearing before Congress that cigarettes don't cause health problems? Unfortunately, it is an exceptional organization that does not commit the faux pas.

So what should those of us who work in CDER do if we realize we have made a mistake? First, we shouldn't panic. Everyone makes mistakes. It's what distinguishes humans from inanimate objects. Next, assuming it is a mistake that has some significance, we should tell someone about it, preferably our supervisor. In that way, we save our supervisor from getting blind-sided about the error later.

Whatever we do, we should not deny the mistake was made. And we must never, never try to cover it up. Occasional errors may or may not get noticed. However, covering up errors often gains headlines. Richard Nixon was not impeached for the Watergate break-in; he was impeached for trying to cover it up.

That brings me to the reason for my column this month. Many of the cases that come to my desk have a history of one or more errors that could have been avoided by CDER staff. Once in a while, those errors form the basis of an appeal, or, at least, lend credibility to a company's complaint.

Yet, rarely do I hear anyone admit in a meeting with the distressed party that any mistakes were made. Sometimes they are glossed over, and other times they are explained in a manner that absolves an individual but still leaves the Agency in a bad light.

Invariably, the company representatives are incensed, making an amicable resolution of the issues more difficult. You won't see company representatives turn red and pound the table, given the realities of the regulator-regulated relationship. However, they become more entrenched in their positions and less amenable to meeting the Agency half way. I wonder, if those meetings had opened with an admission that mistakes were made and regretted, how much time, resources and ill will could have been saved.

We say that individually we want reputations for honesty, credibility and trustworthiness. The CDER operating principles also seek to establish such a reputation for our organization. Admitting our mistakes, both individually and organizationally, is the key to attaining that reputation.

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An Opportunity for the Taking

Too often people regard training as something external that is done to them. Training and development, if they mean anything, come from within. Courses and programs facilitate the process, but learning and development occur within us.

Sometimes we feel so pressed by daily work that we let training and development opportunities go by. I'm not talking about training courses, necessarily, but also about opportunities to learn in our jobs by taking the extra time to research questions that arise. One of the benefits and joys of working at FDA is the opportunity to be exposed to a steady flow of new information and new experiences.

Some of us are contented with our current positions and some are searching for a new path to advancement or fulfillment. Either way, development must be a constant in our daily routine. We all need to grow, and growth comes from new challenges.

Sometimes we need a complete break to reassess the direction we want to grow in. If you find yourself in that situation, or even if you just like the idea of an intensive growth path within FDA, I highly recommend an Agency program, the Leadership Development Program. The opportunity to apply for the program comes only once every two years, and that time is now.

On June 1, an e-mail was sent to everyone announcing that applications will be accepted for the FDA Leadership Development Program through July 27. The LDP entails training and developmental assignments, generally consuming 12 months, to be completed within an 18-month span. While participants keep their current jobs, they spend only about a third of the time actually in their offices.

Participants' developmental plans are tailored to their individual needs and goals. They generally complete four developmental details of 30 to 90 days' duration each during the program. Most of these details are outside their home organization or center. A wide range of training courses is also available.

All headquarters-based participants serve at least one detail in an FDA field office, and field participants come to headquarters for one assignment. However, those are minimum requirements, and it is not unusual for a participant to take a developmental assignment overseas.

The LDP is highly competitive, with only 15 slots available every two years from throughout the Agency. It is open to all permanent FDA employees in grades GS/GM 12, 13 or 14 and Commission Corps O-4 and O-5. It is paid for and coordinated by the FDA's training division and is guided by an Agencywide committee, soon to be chaired by Dan Casciano from the National Center for Toxicology Research. The committee has representatives from each center and Office of Regional Affairs, plus EEO and other Commissioner-level components. This committee interviews the candidates and makes the selections.

Graduates of the program are enthusiastic supporters and are glad to talk about their experiences. Before applying to any developmental program, it is wise to talk with some graduates to get a first-hand view of how it helped them, what they liked most and least about the experience and to find out if it is right for you. I have been the CDER representative on the committee for more than a decade, and I am always happy to advise CDER applicants on the process.

There was a joint CDER/CDRH forum on June 28. If you couldn't attend, just ask me for more information, and I'll be glad to talk with you about the program (MORRISONJ, 4-5443).

Applying to the program is in itself a valuable learning experience, because it makes you think about your career goals and how you plan to attain them. If you don't apply now, you'll have to wait until 2003.

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Reserve Disdain for Supermarket Checkout

About the only enjoyment I get from shopping at the supermarket anymore is reading the headlines of the tabloids while waiting at the checkout counter. It's the only way I can catch up on the latest Elvis sightings and the mating habits of extraterrestrials. It's amusing, because the stories are so over the top that they don't threaten my smug comfort in my own knowledge base.

Reading serious scientific publications, on the other hand, can be an unsettling experience. Every new issue of Scientific American pokes a few more holes in my intellectual armor, which by now has more patches than the Mir space station before it burned up in the atmosphere.

We like to think that we are enlightened and open to new ideas. After all, that is the essence of science. We in CDER frequently express our openness to and nurturing of new concepts in drug development. But on an individual level, when new ideas clash with our personal concepts of reality, problems can arise.

It's easy to understand why we are loath to abandon old ideas for new ones. A lot of our inner tranquility and peace of mind comes from a confidence that we know certain things about how the world works. Then someone comes along and pulls a loose thread in the fabric of our knowledge. We see our protective clothing start to unravel, and we react defensively. This phenomenon is universal. Consider, for example, how long the Australian researcher, Barry Marshall, had to struggle to get the international medical community to accept his proof that H. pylori causes most ulcers.

When we come upon a new therapeutic entity, it's only natural to try to fit it into the fabric of our previous experience. It's unrealistic to expect that we can deduce the mechanism of action of such a new entity, but we all try. We try despite knowing that many drugs make it all the way through development to approval and marketing, and we still don't have a clue about their mechanisms of action.

Clearly, an investigational new drug should not be put on clinical hold simply because the reviewing division finds the drug's postulated mechanism of action implausible. However, it wouldn't be totally irrational to argue that if a proposed remedy cannot possibly work, and if it carries any risk, then it is unreasonable to allow patients to be exposed to it. But if the assessment that it cannot work is erroneous, then it is unreasonable not to allow patient exposure to it for clinical studies.

Thus, the difference between a drug regulator being a heroic public protector or a dangerous obstruction to the public health can be the quality of his or her knowledge. Unfortunately, it is one of life's persistent truths that we all know substantially less than we think we know.

There is a lot of room for judgment in drawing regulatory lines and in weighing benefits and risks. In using our judgment, we inevitably involve our own values and biases. We can't eliminate them, but we can be aware of them and keep them from exerting an inappropriate influence on our decision making.

We must be careful that our own views and biases about a new drug don't color risk-benefit decisions, not only in initial Phase I trials, but throughout the drug review and regulatory processes as well.

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Tolerance

We in CDER are truly blessed to be a part of a multicultural, multiethnic and multidisciplinary staff working together toward a common mission. In this troubling time, as we try to comprehend the enormity of what has happened and what we as a nation should do, we all must keep in mind the vision of America as a land of opportunity and a sanctuary for peoples from around the world.

At critical times in America's history, we have lost sight of that vision. In searching for someone to punish for unprovoked attacks, whether it be Pearl Harbor, the hostages in Tehran or the World Trade Center and the Pentagon, some have lashed out at those whose only connection with the perpetrators was a religion, a skin color or an ethnic ancestry.

We can be assured that our leaders are taking actions that will bring the real perpetrators and their abettors to account. These actions, as the president has made clear, will take time.

In the meantime, we may see acts or hear expressions of religious or ethnic intolerance. Such intolerance stems from ignorance and from a lack of close contact with people in whatever group is being disparaged.

Thinking back to the Oklahoma City bombing a few years ago, when the perpetrators were identified, we did not hear of incidents of intolerance against white males. I believe that was because everyone knew many white men who were good, so that the evilness of the act was associated only with the individuals involved and the fringe organizations that condoned the bombing.

Because we in CDER have daily contact with people of all races and religions and witness their enormous contributions to American society, we tend to forget that many of our fellow citizens do not. Each of us, especially those of us who are not of the Islamic faith or of Middle Eastern ancestry, should accept as a moral imperative to speak out against any intolerance. When we do, we will be paying homage to the victims of the attacks, who are of all races, religions and ethnicities.

I have not heard of any incidents of ethnic or religious intolerance in CDER following the recent attacks, nor would I expect such incidents here. But if anyone has ideas about how CDER can help in combating such intolerance in the larger community, please e-mail me (MORRISONJ).

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Annual Report: Process Problems, Unfairness Top Complaint List

Recent history is counted as the time before Sept. 11 and the time since. This annual CDER Ombudsman's report is mostly from before that fateful day. It's too early to tell what effect, if any, the attacks will have on the rate or kinds of complaints in the future. Therefore, this report reflects business in the good old days.

The number of cases and complaints stayed within the ranges experienced in past years, except that e-mail traffic rose again an estimated 20 percent. In keeping with the trend over the past two years, internal complaints represented only about 1 percent of my work. I tabulated the external complaints using the same categories as previous years for better trend identification. As you can see, the percentages in each category were consistent with the preceding two years, but there are some apparent trends worth noting.

First, it was gratifying to see that the previous upward tick in uncivil or unhelpful interactions was reversed. I hope we are on our way to reducing it to zero. Complaints about timeliness continued to decrease, not only for user fee applications but also for generics.

On the negative side, the biggest increase in complaints this past year, both in percentage and importance, was the access issue. Most of these involved a failure to grant timely meetings or a failure to return phone calls within a reasonable time. Some of the process complaints also involved meetings. These included inadequate or late minutes, failure to resolve disagreements about what was said and other deviations from the meeting MaPP, which is available at http://www.fda.gov/cder/mapp/4512-1.pdf.

Complaints about meetings came from all segments of the drug industry, large and small firms alike. In talking with project managers, it is clear that meetings and minutes of meetings are a tremendous workload burden. The Center holds more than a thousand meetings a year with sponsors of new drug applications.

People in industry devote a lot of resources to preparing for and participating in these meetings, because they view them as absolutely vital to the drug development process. Whatever resources we spend on assuring that all parties walk away from the meetings with the same messages is well spent.

As I have said before in this column, well-written and timely minutes that reflect the understanding of the participants can save months of work for us and the applicants.

If you have a complaint or a solution to a problem, please send me an e-mail or give me a call (morrisonj@cder.fda.gov, 301-594-5443).

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News Along the Pike
CDER Office of Training and Communications (HFD-210)
Parklawn Building, Room 12B-31

Editor: Norman "Joe" Oliver

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