1.

Not communicating with the FDA

2.

Avoiding the safety issue

3.

Lack of planning

4.

Omitting data or including unnecessary data

5.

Not paying attention

6.

Not documenting manufacturing processes

7.

Ignoring the investigators

8.

Forgetting conflicts of interest

9.

Hiding something

10.

Being too eager to disclose to the public

11.

Not thinking globally

12.

Not thinking about electronic submissions

13.

Rushing

14.

Not choosing wisely

15.

Filing a drug that is not needed

FDA, Food and Drug Administration.

Reprinted from Boersig C. Why NDAs fail: 15 pitfalls and how to avoid them. R&D Directions. 2003;Feb:26-42, with permission of AdvanceStar Publications.

1.

Some companies rely too extensively on external industry benchmarks instead of focusing more on internal benchmarking data in assessing the company and to make decisions.

2.

Draft product labels (i.e., package inserts) are used for a number of years prior to preparing the regulatory submission, which leads to misleading impressions about the drug and its development because they include hoped for, rather than demonstrated, data.

3.

Many companies do not use the best development criteria (i.e., minimally acceptable criteria) for making decisions to advance or terminate a drug. Some use ideal, realistic, or desirable criteria, although some companies do not use any formal criteria.

4.

Not systematically creating a system to capture Institutional Memory in order to decrease the number of mistakes made by new or inexperienced staff. When experienced or senior staff retire, move, or die, is their learning lost, or is it captured to help prevent people from repeating errors made in the past? Are staff adequately trained?

5.

Failure to use “Zero-Based Inclusion Criteria” in creating clinical protocols. Too many people take the last protocol written and simply add on a few more criteria without awareness of how this impacts the size of the population available for entry into the trial.

6.

Failure to avoid “procedure bloat” in creating clinical protocols. Too often, the last protocol written is used as a model, and a few more procedures to be done during the trial are added for evaluation of new effects, without considering the need and importance of the data to be collected.

7.

Conducting excessive monitoring visits during a clinical trial when a smaller number would suffice. This is particularly true for large simple trials when only once-a-quarter visits are needed. (Even the FDA has expressed amazement on numerous occasions at the waste that occurs in this area.)

8.

Conducting unnecessary compassionate plea protocols without a careful review and assessment of whether the value of the data obtained justifies the efforts to be expended. While many discuss the “ethical responsibility” to help those who approach the company, few companies consider that those few patients who will be helped come at the expense of time delays caused by such programs, which means that many more patients will not receive the product (and any medical benefits) for a longer time period.

9.

Not reacting immediately to potentially serious adverse event signals until the signal is apparent to everyone in the medical community. A company must insist that it will know more about its own products than any other group or agency. This means using more active drug surveillance methods in Phase 4 and not merely relying on passive surveillance. Take immediate actions when issues arise or a possible signal is detected. No one wants to be accused by watchdog organizations of something the company was unaware of but should have been known. It may be too late at that time to start a clinical trial to evaluate an issue, and the issue often becomes rapidly elevated to a major problem.

10.

Not anticipating potential problems that may be observed in Phase 4 and developing a prospective risk management plan to monitor results of one’s drug after marketing (e.g., if one is aware of elevated liver enzymes in Phase 3, it is critical to develop a monitoring plan to learn the numerator and denominator of both liver transplants and hepatic deaths after marketing, even if none have previously occurred).

11.

Allowing staff to plan work to an excessive degree without a sense of urgency about conducting work.

12.

Allowing silos and fortresses to be built in clinical and other functional groups and not effectively maintaining positive internal teamwork and communications.

13.

Failing to develop methods to prevent tangents from being adopted and followed.

14.

Creating minutes of meetings that are sent for review and finalized but rarely or never used as opposed to creating lists of points of agreement and action points, with the responsible person and due dates listed, and then using this report as the next meeting’s agenda.

15.

Creating development plans and budgets without sufficient critiques, which leads to frequent revisions.

16.

Forming a data safety monitoring board without having a member who understands both regulations and drug development who can prevent inappropriate decisions by academicians who are inexperienced in pharmaceutical development.

17.

Spending time and money on “nice to know” clinical trials as opposed to “need to know” (i.e., essential) trials.

18.

Allowing insufficiently reviewed and considered protocols to be approved, which leads to an excessive number of amendments.

19.

Allowing too strong of an academic environment to flourish in one or more departments at the expense of a sense of urgency and focus on activities that will get the company’s products to market more rapidly.

^aMany of the points listed would apply to most other functional areas in a company.

FDA, Food and Drug Administration.

1.

Using traditional, unimaginative, and obvious regulatory strategies and approaches instead of seeking the most rapid, creative, and efficient approaches. Some of these approaches may never have been considered, but if they make sense, it is up to the company to defend them and try to convince regulatory agencies of their validity (e.g., using a meta-analysis as a pivotal trial, using surveys to obtain supportive data).

2.

Creating “fat” New Drug Applications and other marketing applications instead of determining how lean they can be and then validating the company’s perspective with regulatory agencies.

3.

Creating too “lean” of a marketing application instead of reaching an agreement ahead of time with an agency as to what studies and details are acceptable for the application.

4.

Not stressing the public health message (i.e., medical need) in all executive summaries of clinical documents sent to regulators and not working this message into discussions with the agency in an attempt to win the members’ hearts and minds.

5.

Skipping essential Phase 2 clinical trials and gambling that a Phase 3 pivotal trial will be successful to expedite a regulatory filing, even though many methodological questions for a protocol (e.g., top of the dose-response relationship, best patient population to study, how to titrate and taper the dose most effectively) are not yet known with any degree of certainty.

6.

Making assumptions about what the FDA actually meant by a statement or what the agency wants and/or expects the company to do and will accept in a marketing application.

7.

Not summarizing all agreements and any action points at the end of every meeting with regulators.

8.

Failing to ask the question: “What can we do that will get this product to market faster than anyone has previously thought possible, and what makes sense given the various regulations, guidelines, and practices?” But instead asking: “What will the regulatory agency allow us to do, and what are the regulatory requirements that we must fulfill?”

FDA, Food and Drug Administration.