1. business and industrial
2. pharmaceutical industry

Why NDAs Fail - 15 pitfalls and how to avoid them
Getting a new drug approved is getting harder. Although the FDA is
approving new drugs faster, the regulatory agency is approving fewer new
drug applications.
by Charles Boersig
Getting a new drug approved is becoming more difficult. Although the FDA has gotten better at
approving drugs and approving them faster, the regulatory agency is approving fewer new drug
applications. Complicating the process are many snags that could be avoided. There are 15 big
mistakes that companies commonly make in filing a new drug application. Pharmaceutical
companies can avoid these mistakes by paying more attention.
1. Not communicating with the FDA
The most urgent advice that experts give pharmaceutical companies is to communicate early and
often with the U.S. Food and Drug Administration, their most important audience. Every company
is entitled to meetings with the regulatory agency. The Modernization Act directs the FDA to meet
with sponsors and applicants for the purpose of reaching agreement on the design and size of
clinical trials intended to form the primary basis of an effectiveness claim in a new drug
application or in a biologics license application. Among the meetings that pharmaceutical
companies can request are a pre-IND meeting, end-of-Phase I meeting, end-of-Phase II/prePhase III meetings, and pre-NDA/BLA meetings. The companies can also request a meeting that
is immediately necessary for an otherwise stalled drug development program to proceed. These
meetings are reserved for dispute resolution meetings, meetings to discuss clinical holds, and
special protocol assessment meetings.
Where some companies go wrong is in not holding those meetings at all or not holding effective
meetings. For a meeting to be effective, experts say, companies have to ask the critical difficult
questions and listen carefully to the answers. Before the meeting companies have to formulate
specific questions so that they come away with answers that can enable them to continue with
their product development.
“Listening at the FDA meetings is critical ... not selective listening, but listening and then
evaluating the minutes, especially at the key meetings, and making sure that what was heard is
what the FDA said,” says Louise Shibley, VP of regulatory and technical services at Quintiles
Transnational Corp. (quintiles.com), which provides professional services, information, and
partnering solutions. “Companies should not be afraid to go back and get clarification on things
that they may not agree were said. I can’t emphasize enough the partnership that sponsors are
entitled to have with the FDA.”
The FDA encourages the industry to start communications early in the development process,
before they file an investigational drug application asking for permission to begin their clinical
trials.
“First is a pre-IND meeting before the product goes into man,” says Gerald F. Meyer, senior
consultant at AAC Consulting Group Inc. (aacgroup.com), a subsidiary of Kendle International
that provides support and assistance to industries regulated by the FDA and similar international
agencies. “If the company handles the pre-IND meeting right, it can get an insight into exactly
what the review division believes the company will need to develop the product.”
Inexperienced, intimidated, or ambivalent sponsors may not always use meetings effectively. The
FDA can provide insight and advice on trial design and opportunities that developers may have
overlooked. The FDA can help drug developers understand their product’s potential for special
designations such as priority review and fast track.
Drug developers must understand that the questions asked of the FDA are just as important as
the information presented to the regulatory agency. Failing to ask critical questions because of
uncertainties or not formulating specific questions can prevent sponsors from finding answers that
will enable them to continue with their product development.
“It’s so important to know the customer,” says Audrey F. Jakubowski, VP, regulatory affairs, at
SuperGen Inc. (supergen.com), a pharmaceutical company dedicated to developing and
commercializing products intended to treat life-threatening diseases, particularly cancer. “And the
FDA is ultimately the customer. The FDA is the gatekeeper, and it’s important that the companies
build a dialogue.”
Ms. Jakubowski spoke with R&D Directions as SuperGen is in the process of filing a rolling new
drug application for its anticancer drug Orathecin (rubitecan). Orathecin is being filed as an oral
chemotherapy compound in the camptothecin class for the treatment of pancreatic cancer
patients who are refractory to available therapies. The submission will occur on a rolling basis
and is expected to be completed by the end of the first quarter of 2003. The first module
submitted contained the chemistry, manufacturing and controls section. In November 2002, the
company was granted a fast-track designation for Orathecin. Fast-track designation means that
the FDA will facilitate and expedite the development and review of the application for the approval
of a new drug, if it is intended for the treatment of a serious or life-threatening condition and
demonstrates the potential to address an unmet medical need.
Meetings with the FDA can provide clues to how companies can file a new drug application that
will not be rejected. One of the snags arises when companies decide to disregard what the FDA
has said in the meetings and not follow through on the FDA’s direction.
“Oftentimes it’s just a failure to follow the advice that the FDA has given to the company,” says
Alberto Grignolo, Ph.D., president, worldwide regulatory affairs, Parexel International Corp.
(parexel.com), an outsourcing organization. “I would say communication and trust are absolutely
essential to make sure that, in fact, the company understands what the FDA wants.”
ImClone Systems did not follow the FDA’s advice and ended up with a rejected new drug
application.
“The FDA required the company to do a particular study and the company did not do it, and
submitted the NDA without it,” Dr. Grignolo told R&D Directions. “What is ironic about that is that
the drug in question, Erbitux, is for an unmet medical need and in spite of that the FDA is not
willing to cut ImClone a break. In fact, the agency is requiring the company to do the appropriate
studies that have been requested. Sometimes, even though there is an urgent medical need, the
FDA will take the view that unless the data are there it is not in a position to approve the drug.”
The companies filing the new drug application must be aware of key issues that arise in the
development process and it is essential to relate these issues to the FDA. A manufacturing
change following Phase III for a different formulation may be significant. If this change is not
communicated to the regulatory agency and the issue is not covered adequately in the new drug
application, problems can occur. But before the FDA is made aware, those inside the company in
charge of the filing must be made aware. Cross-disciplinary coordination inside the company
through the development process is critical to the success of the application.
Once in the meeting, the companies must make the best use of the time that the FDA gives them.
“It’s important that the companies take advantage of the agency meetings,” says Ella L. Toombs,
M.D., a former dermatologic reviewer at the FDA’s Center for Drug Evaluation and Research.
“And in taking advantage of those meetings, they should try to use the time wisely and to the best
of their ability. They need to keep their presentation short because the agency staff already has
read the information so they already know. The agency is going to have certain concerns that it
would like to have addressed.”
Companies should focus on addressing those concerns. It would be better, Ms. Toombs says, if
companies allotted more time in getting the FDA’s questions answered and following through with
any agreements that have been made with the agency than discussing elements that the agency
already knows. The companies need to do what the agency requests, they must attempt to be
nonconfrontational, less subjective, and more objective.
When companies file a new drug application, they need to follow to the letter the explicit
directions that the FDA provides in the Code of Federal Regulations, Title 21, subpart B. The
application should be clear and succinct and well-organized so that the reviewers can find their
sections easily, see the sections that belong to other disciplines, and not have any problem in
locating answers to questions.
“Reviewers are human beings; it makes them look at the application in a different light if they
cannot locate answers to questions,” Dr. Toombs told R&D Directions.
The experts advise pharmaceutical companies to do good work. And this means providing an
NDA that is reviewer friendly, easy to navigate, easy to review, and well-indexed.
“We need to make more changes and we need to design succinct, clever studies that are based
on good science and only do those,” says Brian Dickson, who is chief operating officer, Covalent
Group Inc. (covalentgroup.com), a research management and drug development organization.
“That’s clearly what the FDA is looking for. It’s an opportunity for us to reduce research and
development spending and time, if we take the time to plan appropriately and do good science.”
The FDA’s primary goal is to bring new, safe drugs to the market without being a roadblock to
progress.
“In the last decade, the FDA has organized itself in a better fashion,” says Gary Feiss, VP,
regulatory affairs and medical writing, Covalent Group. “In fact, the NDA review times have come
down. The agency is taking great steps to partner with industry in the development process.”
In the dialogue with the FDA, companies should try to avoid placing the FDA in a defensive
position. They need to open a productive and constructive dialogue with the regulatory agency to
clearly identify concerns and in a collaborative manner forge a plan to get where they need to be
as soon as possible. If the filing was deficient, bringing that to the public is not going to help the
company’s case and put the agency on the defensive.
2. Avoiding the safety issue
In addition to written reports of each trial, a new drug application must contain an integrated
summary of all available information received from any source concerning the safety and efficacy
of the drug. Research-based pharmaceutical companies and the FDA take extraordinary
measures to ensure the safety and efficacy of all approved prescription medicines in the United
States. Still, unexpected safety issues arise.
“The FDA has one standard for demonstration of safety, and that is that the benefit must
outweigh the risk,” Mr. Meyer told R&D Directions. “And that’s the standard that they follow
whether it’s a copy, or a me-too drug, or whether it’s the first of its kind.”
There is an increase in postapproval trials primarily aimed at confirming the safety of a newly
approved drug.
“The FDA has now become more concerned with the safety of candidate drugs,” Dr. Grignolo
says. “The agency wants to not only have evidence of safety before approval, but it also
recognizes that large postapproval studies can provide a lot of information about the safety of
newly approved drugs.”
It is also possible that if a new drug application does not include a postmarketing surveillance
plan, the FDA may not be comfortable about putting the drug on the market unless the company
has committed to conducting postapproval studies.
“It is entirely possible that the FDA would withhold approval until the company has a satisfactory
plan in place,” Dr. Grignolo says.
One drug that failed to establish a good risk/benefit profile was Bristol-Myers Squibb Co.’s
antihypertensive Vanlev (omapatrilat). The FDA’s Cardiovascular and Renal Drugs Advisory
Committee met July 19, 2002, to discuss the new drug application for Vanlev, awaiting approval
for the treatment of hypertension. Vanlev was not recommended for approval by the committee.
Committee members were concerned about unpredictable, potentially fatal side effects,
especially angioedema. The committee’s decision was a setback for Bristol-Myers Squibb
(bms.com).
The advisory committee was asked to give its opinion on the approvability of Vanlev to treat
hypertension. Omapatrilat is an inhibitor of angiotensin converting enzyme and neutral
endopeptidase. Reviews of chemistry, pharmacology, toxicology, and biopharmaceutics
presented no barriers to marketing approval. Omapatrilat clearly lowers blood pressure. During its
initial development, an increased risk of life-threatening angioedema was noted for patients taking
omapatrilat compared with other antihypertensives. Angioedema is a localized swelling that
generally affects the face, throat, lips, or tongue that can be triggered by food and commonly
used drugs such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory
agents, and some antibiotics.
To avoid safety-related delays in approval, drug developers need to pay attention to detail.
Because side effects can vary by the race or gender of patients, subset analysis is important for
approval in the diverse U.S. market. When companies file a new drug application, a common
pitfall is that safety has not been determined sufficiently for different subsets of the population.
Most companies do not conduct good enough subset analyses and this delays drug approval.
“The FDA analyzes the data for many different subpopulations even if the company doesn’t,” Mr.
Dickson told R&D Directions. “And the company doesn’t want a surprise. The company doesn’t
want to unknowingly find that the FDA did a subset analysis and found that the adverse event
profile in patients over 55 is four times that of patients under 55 for example. The company needs
to know that going in.”
The data in the new drug application have to take into consideration the target population.
“If all data coming from abroad had been collected in white Caucasian patients, this would not be
representative or relevant to the African-American population in this country,” Dr. Grignolo says.
“And that has been an occasional reason for the FDA not wanting to approve the NDA because
the data were not directly relevant to all of the U.S. population.”
3. Lack of Planning
Pharmaceutical companies have to have a strategy for the product. They must know early what
they are going after in terms of what is most critical and important for the drug and then designing
that into the program early with a focused and concerted strategy to achieve it. The new
environment that has developed during the past few years at the FDA presents an opportunity for
the pharmaceutical industry to talk science with the agency and design proper and succinct
studies, and not many of them. Experts advise against an old standard: filing a new drug
application with three indications hoping that at least one will be approved.
“This is kind of old,” Mr. Dickson says. “There are some old traditions that really should die.”
Three indications require the submission of extra data, which will slow down the review process
and cost the company money.
“That means the FDA has to review the additional information, get annoyed, and throw it out,” Mr.
Dickson says. “And the companies have to prepare the data. That’s a waste of time.
Another old standard that should be adjusted is the thinking that a Phase III trial has to be
conducted. Conducting all the phases is a guide, not a mandate.
“Conducting Phase I, Phase II, Phase III, and Phase IV is a good guide, but it is a guide that’s two
decades old,” Mr. Dickson says. “They don’t necessarily have to do Phase III. If they are
developing an oncology compound, they can conduct an extended Phase II and submit. If it’s an
oncology compound, the benefit and the risk/benefit are much more in favor of an abbreviated
program.”
One of the important items that will snag a new drug application is not having draft labeling.
Pharmaceutical companies need to begin with the end in mind. Developers need to begin the
clinical process having a draft of the label and designing studies that support the desired claims.
The end being the label. The label will dictate primarily what their indication will be but also what
the adverse events are and how they support the indication.
Pharmaceutical companies need to grab the one indication that is reasonable and be
conservative. They can always expand on that indication with a supplement.
“They need to be objective and make sure that what they’re considering can go in the label and
that there isn’t any information that would be of a marketing nature,” Dr. Toombs says.
In addition to making sure the endpoints of a clinical development program are specific and clear,
drug developers need to demonstrate that a drug improves upon existing products.
“It’s particularly important to differentiate the product from another product if it’s not the first on the
market,” Mr. Dickson told R&D Directions. “And if, in fact, the company is going to differentiate it,
that’s how they need to do it. They need to do it in their expected labeling.”
A mistake some drug developers make is waiting until clinical trials are complete to make
decisions about the market niche a drug will fill. In addition to jeopardizing approval, poorly
planned endpoints can prevent marketers from fully capitalizing on a drug’s potential.
“Sometimes at the time of NDA preparation the project team gets together with marketing and
they decide how their drug is going to improve upon what’s out there,” Ms. Shibley says. “That’s
not the time to make those desired claims.One needs to do that up front in what can be called the
target package insert so that the studies are designed up front to support the labeling claims.”
Because of the speed at which medical advances take place, even the most carefully planned
clinical development program can produce results that do not warrant an approval.
“Sometimes the state of the art in the scientific interest to the particular drug has changed and the
efficacy endpoints are no longer relevant,” Dr. Grignolo told R&D Directions. “In the fast-moving
field of virology, for example, efficacy endpoints that were relevant three years ago may no longer
be relevant. The company may in good faith conduct trials, but [the trials] may be obsolete the
moment they are finished.”
Some decisions about planning development endpoints must ultimately be made based on the
developer’s financial status, business strategy, and capabilities. Opinions differ on whether it is
best to take the quickest path to approval or to target more complicated but potentially more
lucrative indications.
Sometimes a company adopts the strategy for getting the easiest indication first and the
blockbuster indication later. Most of the time, a company goes for the indication that makes the
most attractive approval.
Regardless of the development strategy adopted by a drug sponsor, early planning is one of the
most essential steps on the way to a successful new drug application.
“From my point of view, the biggest problem is lack of planning,” Mr. Dickson says. “Part of the
problem is that everybody’s under pressure to do things immediately, but time is not taken to
consider the planning process appropriately.”
“Of course, there should be no information that’s misleading. They need to support that indication
by assuring that the study design is based on parameters that are the standard and that can be
easily validated. It’s better that there be no attempts to reinvent the wheel. And maybe take a look
at studies that were done previously for that particular drug category or that particular indication
and follow what happened in those studies as opposed to trying to reinvent the wheel.”
The time to decide what will differentiate the new drug from competitors on the market is not
when the new drug application is being prepared but when the clinical studies are being
designed.
“Drafting the target core product information reasonably early can’t be underestimated,” Mr. Feiss
told R&D Directions. “Deviations from that late in the game are very detrimental.”
Pharmaceutical developers must focus on designing clinical programs that meet the regulatory
requirements and the target labeling claims without going into excessive costs and multiple
studies that don’t need to be done.
“The first thing that they have to do is develop a protocol that will answer the questions that will
demonstrate safety and effectiveness,” Mr. Meyer told R&D Directions. “That may sound obvious,
but it’s easy for people to develop a protocol and say, ‘Wouldn’t this be nice to know and wouldn’t
that be nice to know?’ And pretty soon they’ve got a fairly diffuse set of endpoints. They need a
targeted protocol that will zero in on the data that they need to demonstrate safety and
effectiveness.”
Pharmaceutical companies have to remain vigilant. They have to make sure that they clean the
data as they go along. When the last patient enrolled has completed the medication, a company
can immediately begin to organize the data to submit it.
“One of the common problems is that after the last patient has completed treatment, it takes
some companies anywhere from 18 months to two years or more to clean up the data and get it
submitted,” Mr. Meyer says. “It’s my view that if they’ve done that correctly as they go, they ought
to be able to submit that NDA in 6 to 12 weeks. And that makes a big difference. But they’ve got
to not do unnecessary studies and not have a messy bunch of data to figure out.”
4. Omitting data or including unnecessary data
Some experts say the reason fewer new drug applications are being approved is partly the fault
of the pharmaceutical industry. The FDA prefers well-designed studies. If the studies are well
designed, companies can submit data from fewer studies. What the FDA does not want is many,
poorly designed studies. “The typical NDA for the last 5 to 10 years has had too many studies in
it,” Mr. Feiss told R&D Directions. “Each of these studies costs millions of dollars and takes time.”
Pharmaceutical companies need to identify the critical factors that are required for approval and
required based on the plans for the product.
“A trap that companies can fall into is trying to be too encompassing,” Mr. Feiss says. “The FDA
clearly prefers well-designed studies, and they don’t have to do too many of them. What the FDA
does not like is a mishmash of less well-designed studies.”
Companies have conducted studies and submitted data that are not necessary to gain the
desired indication. For example, to support an additional claim on an indication for an
antihypertensive drug that says “to be taken alone or in combination,” companies have spent
millions of dollars. According to experts, the FDA will routinely allow that claim on all
antihypertensive drugs, with or without studies. The problem, besides spending money that does
not need to be spent, arises when the studies show that the drug does not work in combination. It
is essential that companies identify early what they want to put on their product’s labeling. The
point of differentiation of a product is in its labeling and that has to be considered when a new
drug application is being written.
During the past several years, the regulatory agency has been making strides in finalizing
guidance documents and sharing information even in the draft-guidance stages about what it is
interested in seeing in various therapeutic categories.
“Much of this information has been greatly enhanced through the access of information through
the Internet,” Mr. Feiss says. “The FDA has an excellent Website. Information as to what to do in
designing a program is much more accessible than it used to be. The agency is there to get drugs
approved and on the market, not to be a roadblock. And it is taking great steps to do that and to
partner with industry in the development process. In the current regulatory environment, there are
certain codified opportunities for critical meetings and critical points of discussion in addressing
issues in the development program. That’s a fantastic opportunity for companies, if approached
properly, to expedite their development program and become more focused in their approach.”
5. Not paying attention
Pharmaceutical companies need to start from the beginning; they need to plan what type of
studies they are going to do, what type of meetings they are going to have with the FDA, and
decide what they want to achieve at those meetings and pay attention when the FDA talks. The
FDA will discuss its concerns about the drug and will also show excitement about the aspects of
the drug.
“They need to listen at that meeting to what the FDA says,” Mr. Dickson says. “Some people are
so overwhelmed in what they want to get across to the FDA that they forget to listen. It sounds
trite, but it has caused problems. The FDA will tell them what its interests are. The FDA may get
excited about some of the items discussed by the company. That’s important when the company
does its NDA because the company needs to highlight that. The FDA will also tell them what its
concerns are. That’s important when they are doing their NDA because they need to clearly
address those concerns. They can’t hide from them.”
In planning for meetings, pharmaceutical companies need to plan for audits. Experts warn that if
an NDA has been filed, an audit will be conducted. And the audit may be conducted before
companies submit an NDA.
“The FDA knows that the company is going to submit an NDA at least a year before it is
submitted,” Mr. Dickson says. “The company may get an audit prior to submission of the NDA,
and it may have to plan for it and expect it. If the company does poorly in that audit, it will delay
the NDA.”
Experts strongly recommend that companies do not forget to address the requirements that the
FDA has made during Phase II and Phase III clinical trials. “Don’t forget to fulfill those
requirements and don’t leave things sort of unspoken and undone simply because it’s not
convenient,” Dr. Grignolo says. “The FDA will remember everything they’ve required the company
to do. So be honest with the FDA.”
Not listening is what got ImClone Systems in trouble. In November 2001, Bristol-Myers Squibb
Co. and ImClone Systems Inc. (imclone.com) completed the filing of the rolling biologics license
application to the FDA for approval of Erbitux for the treatment of irinotecan-refractory colorectal
cancer. Two months later, the FDA refused to accept the application, asking ImClone provide
more information on how the company verified that patients in its clinical trials had failed previous
drug therapies. Regulators also wanted to verify that Erbitux was actually responsible for
shrinking patients’ tumors. In February 2001, the FDA granted ImClone Systems fast-track
designation for Erbitux in the treatment of irinotecan-refractory colorectal cancer.
“The FDA looked at the protocol and said it was not good,” says Jim McCord, CEO of Fast Track
Systems (fast-track.com), a clinical development optimization company. “The agency told the
company that it did not know whether the people that the company was claiming were eligible
really were eligible.
“We’re at the one-year anniversary of Sam Waksal’s presentation at the agency conference. And
at that time he was trying to pacify the FDA. And he made it very clear that if ImClone Systems
had paid more attention to talking to the FDA during the process, they wouldn’t have had this
problem. All of the conversation on that seemed to have gone one way. The FDA said do this and
the company didn’t. Getting the FDA aboard in this is really important.”
6. Not documenting manufacturing processes
The approval process for new drug and generic drug marketing applications includes a review of
the manufacturer’s compliance with the current good manufacturing practices and manufacturingrelated commitments made in the new drug application. FDA inspectors determine whether the
company has the necessary facilities, equipment, and skills to manufacture the new drug for
which it has applied for approval. Decisions regarding compliance with current good
manufacturing practices regulations are based on inspection of facilities, sample analysis, and
compliance history of the company. This information is summarized in reports that represent
several years of history of the company.
The Food and Drug Administration can issue a warning letter or initiate other regulatory actions
against a company that fails to comply with current good manufacturing practice regulations.
Failure to comply can lead to a decision by the FDA not to approve an application to market a
drug.
Manufacturing concerns for Eli Lilly and Co.(lilly.com), have already delayed the approval of Cialis
(tadalafil) and other near-term drugs. Federal regulators have been conducting inspections in
several of Lilly’s manufacturing facilities in Indiana. At one facility, FDA officials are inspecting the
Cialis and Cymbalta (duloxetine) bulk manufacturing processes and parts of the atomoxetine
process. At another site, the FDA is inspecting the company’s dry-products facility where Cialis,
among other products, is manufactured. In addition, the FDA is conducting a reinspection and a
general good manufacturing practices inspection of the company’s sterile parenteral facility.
Although Lilly executives noted in November 2002 that manufacturing is not a barrier to approval
since Cialis will be manufactured outside Indianapolis, final U.S. approval of Cymbalta is
contingent upon labeling discussions and successful completion of a preapproval manufacturing
inspection at the Indianapolis dry-products facility.
Lilly received a Form 483 outlining 50 additional observations from the FDA following its
reinspection of certain manufacturing facilities in Indianapolis in connection with pending newproduct approvals for Zyprexa IntraMuscular (olanzapine) and Forteo (teriparatide). The company
holds approvable letters from the regulatory agency for these two drugs. Although Forteo was
approved Nov. 26, 2002, FDA approval of Zyprexa IntraMuscular continues to be contingent on
resolving all manufacturing issues to the regulatory agency’s satisfaction.
Lilly has been told by the FDA to continue to simplify its quality processes, enhance its technical
expertise and oversight, and improve its ability to identify the root cause of manufacturing
deviations.
“We accelerated making these changes in Indianapolis late last year following the previous FDA
reinspection, but we have not completed implementation and thus the full impact of these
changes has not yet been seen,” says Pedro P. Granadillo, senior VP, Lilly. “We believe that we
can address these concerns and meet the regulatory agency’s expectations. We share with the
FDA the same ultimate goal of raising our global manufacturing and quality operations to the
highest standards.”
Failure to plan for safety audits is among the reasons that approval may be delayed or denied.
“Companies need to plan for audits,” Mr. Dickson told R&D Directions. “Companies will get an
audit when they’re doing an NDA.”
Drugs must be manufactured in accordance with good manufacturing practices, and the FDA
inspects manufacturing facilities before a drug can be approved. If a facility is not ready for
inspection, approval can be delayed. Manufacturing deficiencies found need to be corrected
before approval.
“It’s critical that companies have a mock audit of their facility before submitting the NDA,” Mr.
Dickson says. “Sometimes that involves two mock audits, and they must be conducted by
external people. The company can’t have an internal group conducting the audit. There are many
groups that specialize in doing just that. It is even more important, in fact, critical if the product
happens to be a biological because biological inspections are way above, in terms of
rigorousness, an ordinary product, a solid-dose or liquid-dose form pharmaceutical.”
Changes or refinements in manufacturing practices should be made as early as possible, brought
to the attention of the FDA before submission of a new drug application, and documented in the
new drug application.
Process validation is another aspect of the new drug application that drug developers must pay
close attention to.
“A company can have the best clinical data in the world, but if the product information hasn’t been
documented, the application is going nowhere,” Ms. Shibley says.
7. Ignoring the investigators
In addition to paying close attention to manufacturing processes and facilities, monitoring trial
sites to determine if there are any instances of noncompliance with study protocols is essential.
Drug developers should expect inconsistencies in every trial and must be sure to address and
explain these in meetings with the FDA and in the new drug application. This is particularly
important for small companies that rely on outsourced clinical trials.
“By design, a small company decides to contract out work to other companies,” Ms. Jakubowski
says. “It becomes very difficult to know what these people are doing on a day-to-day basis at the
clinical sites.”
Clinical investigators must always be ready to host an inspection. Visiting sites, appointing
someone to monitor trials, or enlisting the help of companies that monitor trial sites are some
options available to trial sponsors.
“It’s very critical to have a prospective clinical investigator inspection strategy,” Mr. Dickson told
R&D Directions. “Generally speaking, through the clinical program, companies will know which
sites may have had some issues that need to be addressed from a GCP standpoint.”
Compliance with protocols at clinical sites can be improved if drug developers have laid out clear
objectives and procedures early in the development process. “If there isn’t a rigorous structured
approach to defining a trial, the documentation is likely to vary trial by trial,” Mr. McCord says. “At
least things will appear on different pages and different sections. And that makes the reviewer’s
life tougher. That takes longer and causes more disruptions.”
Oftentimes sponsors can anticipate which clinical sites are likely candidates for an audit by
identifying sites with high patient enrollment or sites that have had protocol issues that needed to
be addressed during trials. Monitoring trial sites should begin early, and irregularities or
inconsistencies in clinical protocols should be brought to the attention of the FDA as early as
possible and explained in the new drug application.
“If there have been problems with a particular investigator, it is very important that the sponsor in
the submission bring that up and explain it because the agency could selectively go back and
review any or all of the investigator’s work,” Dr. Toombs, says. “And one would not want there to
be problems found subsequently because it raises questions and forces the FDA to look deeper.”
8. Forgetting conflicts of interest
Even the most carefully planned and monitored clinical development program can experience
delays because of unforeseen conflicts of interest. A good example of a failure to avoid conflicts
occurred in 2002 partly as a result of the difficulty in assembling completely unbiased experts to
review products intended to treat a rare disease.
The FDA’s decision to postpone the review of Fabrazyme (agalsidase beta) and Replagal
(agalsidase alfa) is delaying the market entry of these medicines. The decision reflects an
increased level of scrutiny of pharmaceutical companies and clinical investigators by the U.S.
Food and Drug Administration. Postponing the review highlights the need for full disclosure of
connections between scientists and research sponsors and the difficulty in assembling completely
unbiased scientists qualified to testify about rare diseases. The developers of these drugs,
Genzyme General (genzymegeneral.com) and Transkaryotic Therapies Inc. (tktx.com), are
competing for first approval in the United States. Both products are awaiting approval to treat
Fabry disease. The biologics license applications for Fabrazyme and Replagal have been under
FDA consideration for more than two years.
The FDA postponed the September 2002 meeting of its Endocrinologic and Metabolic Drugs
Advisory Committee. On Sept. 26, the committee was scheduled to discuss Genzyme’s biologics
drug application to market Fabrazyme. On Sept. 27, the committee was scheduled to discuss
Transkaryotic’s biologics drug application of Replagal.
Some experts say the cancellation of the September meeting indicates that the FDA is paying
close attention to new guidelines, issued in February 2002, that emphasize financial disclosure by
advisory committee members. Postponing the product reviews is costing both companies
potential product sales and investor confidence.
The sessions to review the products were rescheduled, delaying potential approvals. Fabrazyme
was reviewed by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Jan. 13,
2003. The committee met to consider Replagal Jan. 14, 2003. The committee voted that
Transkaryotic had not proven that Replagal was effective in treating Fabry disease, but agreed to
accept parts of Genzyme’s clinical trial data for Fabrazyme.
Genzyme had publicly objected to the postponement of the September review, claiming that the
panel members would have been able to reach an objective conclusion about the products. Both
companies had hoped that their products would be approved before the end of 2002.
The reason for postponing the session to review Fabrazyme, according to Genzyme officials, was
the FDA’s concern about the composition of the advisory committee. The FDA said the reason for
postponing had to do with administrative issues. The reason for postponing Replagal’s review
was different. The agency expressed concerns about clinical data, particularly with respect to
pain. The FDA indicated that methodological issues made the pain data uninterpretable and that
data supporting the primary pain endpoint did not support approval. Transkaryotic believes that
these pain data demonstrate an important benefit for patients, but has concluded that the best
approach to obtain a prompt approval for Replagal in the United States is to seek approval on the
basis of its renal and cardiac data. Transkaryotic believes that an advisory committee meeting will
allow the company to address the FDA’s concerns about the renal and cardiac data and
demonstrate the medically compelling nature of these data.
The postponing of the reviews has sent a signal to the pharmaceutical industry, observers say.
Everyone involved with the development and approval process must be ethical and forthcoming
about financial connections with the drug’s sponsor.
Weeks before experts on Fabry disease were to be assembled before the FDA committee,
objections were raised about some of the connections that committee members had with
Genzyme. The Wall Street Journal reported that Transkaryotic objected to at least four “invited
guests,” nonvoting experts that the FDA had assembled to help answer questions from its
Endocrinologic and Metabolic Drugs Advisory Committee. All of the objectionable guests had ties
to people or institutions with a financial interest in the Genzyme drug, these people said.
Genzyme executives acknowledged that a concern was raised about the composition of the
advisory committee, but insisted that the panel would have provided the appropriate expertise
required by the FDA.
“The FDA felt that these potential conflicts of interest had a part in them having to cancel the
meeting,” Bo Piela, spokesman for Genzyme, told R&D Directions. “We obviously opposed the
cancellation of the meeting and objected to any sense that any of the invited experts had any ties
to us.”
Both companies have told R&D Directions that they were responsible for informing the FDA about
the possible conflicts.
“We brought this to the attention of the FDA,” says Justine E. Koenigsberg, director, corporate
communications for Transkaryotic Therapies. “When we reviewed the list of guests invited to
participate at the panel meeting we came to the conclusion that there were conflicts of interest
and we brought them to the attention of the FDA.”
9. Hiding Something
Pharmaceutical companies have to be transparent. In the new drug application, they cannot fail to
address weaknesses in the data up front and put them in perspective. They have to recognize
that there are problems and put them in perspective.
“No NDA is perfect,” Dr. Grignolo told R&D Directions. “There are always some data that don’t fit
the claim of efficacy and safety. There’s always some problem in every NDA, and companies are
advised to own up to these problems.”
One of the reasons drug developers experience safety-related delays at the FDA is a failure to
plan for adverse events or other safety issues. If a drug’s safety profile or adverse events appear
to be systematic and serious, the FDA may withdraw a product from the market. Building riskmanagement programs into new drug applications is an important part of addressing potential
safety issues.
The FDA’s division of surveillance, research, and communication support is a newly formed
division that handles data resources, risk communication, and outcomes and effectiveness
research components of drug safety risk management programs. This division oversees
MedWatch, risk communication research and activities such as medications guides, patient
packet inserts, and pharmacy information surveys, and international regulatory liaison activities
for all drug and biologic postmarketing safety issues. The division of surveillance, research, and
communication support manages the expansion in the use and number of safety and
epidemiologic data resources from the office of drug safety.
In addition, the FDA is creating a new drug safety and risk management subcommittee to the
advisory committee for pharmaceutical science. The subcommittee comprises experts in the
areas of risk perception, risk management, pharmacoepidemiology, clinical pharmacology, clinical
research, and medication errors who will advise the FDA on general and product-specific safety
issues.
The impetus for the creation of the subcommittee is the need for expert advice on complex drugspecific safety issues as well as methods of risk assessment, management, and communication.
These issues play a significant role in FDA’s overall evaluation of the risk/benefit ratio of drugs,
and are common topics of discussion at advisory committee meetings.
Being candid with the FDA about problems and setbacks will signal the developer’s good faith
and interest in working with the regulatory agency. Risk management begins early in the
development process and continues after the filing of the application.
The FDA in recent years has had a great interest in risk management. It is smart these days to
build a risk-management plan into the application because the FDA will often ask for it. This can
make the difference between receiving an approvable letter and an approval letter.
“The most important audience is the FDA” says Donald McLearn, senior VP of Ruder Finn Inc.
(ruderfinn.com), a communications, counseling, and services agency. Mr. McLearn spent many
years at the FDA, where he served as the deputy associate commissioner for public affairs. “Even
when a company is going before an advisory committee meeting, it has remember that the FDA
set up the questions to ask the advisory committee. And the questions and answers can be make
or break for a company. The companies cannot ever believe that the FDA doesn’t stage manage
that whole process.”
10. Being too eager to disclose to the public
The price of a pharmaceutical company’s stock can fluctuate significantly based on financial
reports and the outcome of new drug applications. Pharmaceutical developers need to pay close
attention to the timing and contents of disclosures and announcements to investors and the
public. The companies that tend to be eager about their announcements are the biotechnology
companies, which want to stimulate the price of their stock.
“I don’t know what the motive is,” Mr. McLearn told R&D Directions. “They tend to announce
everything too quickly, sometimes embarrassing themselves, because then it’s public to the world
that they’ve been turned down.”
Mr. McLearn has some advice for these companies: “Don’t announce to the world everything too
fast. Be strategic about announcing to the world when you’re going in with an application to the
FDA.”
Most major companies that have had experience in this area tend to wait until they have good
news to announce. Many lawsuits have been filed during the past year against pharmaceutical
companies for misrepresenting product potential and issuing misleading financial reports to inflate
stock prices. Federal and state securities laws oblige public corporations to disclose accurately,
completely, and promptly all material information that could affect investment prices to investors.
Knowing or reckless misrepresentation or non-disclosure is actionable under the federal
securities laws.
In spite of the strict requirements concerning disclosure, inexperienced companies can hurt
themselves by poorly timing disclosures or announcing every detail of a clinical development
program in the hopes of boosting the price of the stock.
11. Not Thinking Globally
Pharmaceutical companies can avoid dossier planning and compilation nightmares if they
consider preparing the new drug application in a global format. In July 2003, the common
technical document is going to be mandatory in Europe and Japan.
“The FDA strongly expects it,” Ms. Shibley told R&D Directions. “Companies could save a lot of
time in submitting applications in different regions if they start out with that common technical
document format.”
The time to think about filing with the European authorities for drug approval is not when the
company is filing for a new drug application in the United States. Early in the process, the
company needs to decide whether there should be a global submission. If the answer is yet, the
company should start to prepare the common technical document format.
“They won’t have any choice after 2003 in Japan and Europe; that’s something to take into
consideration,” Ms. Shibley says. “Consider electronic submissions to save paper, especially with
the case report forms. And, of course, the whole application can be electronic.”
12. Not thinking about electronic submissions
Some companies do not think about electronic submission in time to have their documents in
acceptable electronic format. They think about electronic submission at the end of the
development process, at which time, the documents have to be reformatted.
“The FDA encourages electronic submissions and the agency will even encourage partial
electronic submission so that the companies can do some in paper and some electronic if they
don’t have the validated electronic systems to submit it all electronically,” Ms. Shibley told R&D
Directions.
Biotechnology companies are recognizing the benefits of using electronic data-capture
technology to streamline data collection during clinical trials and are making plans to implement
the technology. These are the findings of a survey conducted by CB Technologies Inc.
(cbtech.com), which develops and delivers technology tools and services for life-science
companies.
Almost two-thirds of survey respondents acknowledge benefits to implementing electronic data
capture, and biotechnology companies appear to be making preparations to use the technology
— 87% of respondents anticipate that their companies will conduct more of their clinical trials
using electronic methods instead of the traditional paper-based processes for data collection.
New technologies for electronic data capture and global initiatives to develop standardized
documentation for new drug applications represent a new opportunity for drug developers to
speed reviews and maximize product potential. Since the emergence of electronic data capture a
few years ago, clinical trials professionals have recognized the potential for electronic data
capture to enhance the quality and efficiency of clinical data management. But making the
transition from paper-based reporting to a Web-enabled, real-time process requires a significant
evolution in clinical research practice.
The FDA is working with the industry to phase in electronic submissions as companies gain the
required capabilities. The real-time nature of electronic data capture allows a drug sponsor to
continuously examine incoming trial data and detect errors before the NDA stage.
“They’re getting the data fed to them routinely at the end of the day,” Mr. McCord told R&D
Directions. “And if there’s something wrong with it, they see something they don’t like, they can
send a query back to the site and get it fixed electronically.”
Regulatory experts agree that the clinical trials process has to change to take advantage of
technology. Drug development has to become more efficient and productive.
13. Rushing
Smaller or newer companies, such as the biotechnology companies and emerging development
companies, may be more likely to run into problems with the regulatory agency. They lack
experience and familiarity with the regulatory process. “One of the key things is to not submit an
application too prematurely,” says Anthony J. Clemento Jr., VP, scientific and regulatory
consulting, for Covance Consulting Services (covance.com). “We see that especially with some of
the newer pharmaceutical companies, biotechnology companies. They underestimate the rigor
they need to use to develop a drug. What happens is they rush the IND filing to get into clinical
trials. Then they rush to get the NDA or the BLA filed, and they don’t have the appropriate data to
satisfy that benefit-risk assessment that regulatory agencies use for licensure.”
If companies rush a filing, they can expect they run many risks, the worst of all being that that the
FDA refuses to accept the NDA and returns it.
“That would probably be a real disaster,” Mr. Clemento told R&D Directions. “More often what
happens is that the FDA and the company begin to open a dialogue of a series of questions and
answers. And that period, depending upon how poorly the data have been presented and the
seriousness of the lack of data, it may take anywhere from many months to several years to go
back and forth answering questions, providing new data, making clarifications, and responding.”
The FDA refused to accept the new drug application filed by ImClone Systems for Erbitux. This
was ImClone’s first new drug application. Most emerging biotechnology companies are working
on their very first new drug application and the next application may be a few years away. Most
large pharmaceutical companies file at least one new drug application per year and have been
able to gain more knowledge about what it takes to work with the FDA and sometimes predict
what the FDA wants in the new drug application. For the small companies, it is learn as they go.
Getting an NDA approved for them can be a slower process.
“The small companies have one chance and they want to do it right,” Ms. Jakubowski says.
“There tend to be more inexperienced people than experienced people in the small company.
They have to learn really fast. They really do need to wear their running shoes and be somewhat
nimble.”
Small companies are having a harder time with trials. Because the financial markets are no
longer supporting them, they have to start worrying more about advancing their drugs toward the
market. The biotechnology companies have geared their business plan toward what the
investment community wants and not what the FDA wants.
Some biotech companies will announce every step of the way, everything that the company is
doing, good and bad. They have tended to overly saturate the investment community with
information about their product without involving the FDA at all. On the other hand, a major
company such as Merck, will not announce that it is sending in an application to the FDA. They’ll
wait the 60 days to see if the FDA accepts it and then they’ll announce it so they know it’s only
going to be positive news.
“They realize for the first time they have to understand more about trials than they do,” Mr.
McCord says. “It’s hard to see a short-term fix other than getting somebody aboard in those
companies not to do the trial, but who knows how to hold the CRO’s feet to the fire. One thesis
that this company was founded on was that if the companies did a better job in designing the trial,
designing the protocol, that they had a better chance of getting a successful trial executed and a
better chance at the FDA. We give pharmaceutical companies access to a large library of
historical trials conducted by all major pharmaceutical companies.”
Industry experts stress the importance of experienced regulatory professionals. Expertise can be
sought outside the company or developers can take advantage of the regulatory department
within the company to improve interactions with the FDA.
“Regulatory professionals know the hot buttons,” Ms. Shibley told R&D Directions. “They may
know the cast of characters within the FDA reviewing divisions. Companies can use the
regulatory experience and professionals within their product development team to shorten the
approval times.”
14. Not Choosing Wisely
One of the basic principles of filing a new drug application that will lead to drug approval is
conducting research that will make the drug company more informed about all relevant issues.
Pharmaceutical companies should understand the marketplace and the competition. Based on
that research, the companies should wisely select a molecule. Pharmaceutical companies should
design a program that will develop the data to generate a product profile that has clear and
distinct advantages when compared with competing products.
Pharmaceutical companies should understand the requirements for manufacturing to develop a
process that has a good cost-of-goods profile. The companies should generate the data that
demonstrate safety and efficacy in the target populations as best as possible.
15. Filing for a drug that is not needed
The pharmaceutical companies have to become better at bringing innovative drugs to market. Of
all the medicines that the FDA approved in 2002, 11 of 78 were approved based on priority
review, which indicates that the product provides a significant improvement in treatment
compared with products already on the market.
If a medicine is not innovative, it will have a harder time coming to market. New drug applications
for medicines that are not innovative or do not satisfy unmet medical need are especially
vulnerable to delay.
By law, the FDA has to look at the evidence of safety and efficacy of every drug on a level-playing
field, whether the drug is innovative or not. But the regulatory agency takes longer to approve the
standard drugs, those that are not given priority review because they do not add to the arsenal of
treatment and may even take a closer look at the application.
“They have to look at the evidence of safety and efficacy on a level playing field,” Dr. Grignolo
says. “But in fact, when there is not an unmet medical need the FDA will take perhaps a closer
look at risk/benefit ratios and whether a drug is really providing any additional benefit to what is
already on the market.”
Dr. Grignolo has some advise for pharmaceutical companies: Be honest with yourself as a
company. If your drug is a minor improvement on what is available, what is the medical need that
it meets. In other words, if it’s minor is it likely that the FDA would in fact want to approve it? Does
this drug make any difference?
Companies should take responsibility. It is the company’s drug, not the FDA’s drug. It is the
company’s responsibility to execute the studies and collect all the necessary data and make the
case to the FDA. When the FDA does not approve a new drug application, the company should
first look at itself and ask: What have I not done? Where is the weakness in my case? Where
have I not been able to persuade the FDA and how can I do better?
www.pharmalive.com
©2003 Engel Publishing Partners