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FDA in Motion


Pharmaceutical Executive

Pharmaceutical ExecutivePharmaceutical Executive-12-01-2002

Tremendous changes are underway at FDA headquarters in Rockville, Maryland. Whole sections of biologics review moving from one center to another. Regulatory activities being refocused on risk. Restructured roles for agency field inspectors. And a variety of other reforms, many driven by the specter of bioterror. Despite operating for almost two years without a commissioner, FDA is moving full speed ahead with a major reorganization and a new regulatory philosophy.

Tremendous changes are underway at FDA headquarters in Rockville, Maryland. Whole sections of biologics review moving from one center to another. Regulatory activities being refocused on risk. Restructured roles for agency field inspectors. And a variety of other reforms, many driven by the specter of bioterror. Despite operating for almost two years without a commissioner, FDA is moving full speed ahead with a major reorganization and a new regulatory philosophy.

An interview with Deputy Commissioner Lester M. Crawford, who has served as acting commissioner for the past nine months, reveals the purpose, status, and prognosis for those changes-which may accomplish the most sweeping transformation of the agency in decades. (For a look at Crawford's background and accomplishments, see "Sweet Home Alabama," page 40.)

Complementing PE's conversation with Crawford is a preview of newly confirmed FDA Commissioner Mark McClellan's view on FDA policies. It includes McClellan's responses to questions from members of the Senate's Health, Education, Labor and Pensions (HELP) Committee that has jurisdiction over confirmation of the FDA commissioner. The new FDA leader reveals familiarity with many health policy issues and political skill in side-stepping controversial topics-something he may not do so easily once he is in the driver's seat.

Behind the Scenes with Dr. Lester Crawford


Risk-based regulation seems to be an umbrella for many of FDA's initiatives for change. Would you explain the concept?

Crawford: It was established by Congress in the 1938 Federal Food, Drug and Cosmetic Act, which gave "regulatory discretion" to decide what FDA will or won't regulate. You have to announce how you will interpret that-to say that "for good and sufficient reasons" you will either de-emphasize the regulation of something the Act or the 1962 amendments calls for, or that you will not enforce it at all. That implies risk assessment.

Sweet Home, Alabama

We have traditionally rewarded inspectors by the number of inspections they make. That's not the way to do it. It may have been right years ago, but now we need to focus on high-risk products that threaten human health and also raise concerns about bioterrorism.

In the drug approval process, the same thing holds true. We need to be doing risk-assessment across the board. We need to inform the public that although there will always be risk, some things are riskier than others. The FDA commissioner is really the risk manager of food and drugs in the United States. No more, no less. In fact, as a deputy commissioner, I wouldn't mind being called deputy risk manager. That would be great because it would convey what we are trying to do.

PE: So, risk-based regulation means, for example, that you might choose to reduce inspections for a certain class of manufacturing plants?

Crawford: That's possible. Our biggest challenge in risk assessment has been managing field operations. We are ready to rethink how we want to organize the Office of Regulatory Affairs, because it now has approximately 4,500 personnel. That's big news for two reasons. First, it's the largest number we've ever had. Second, we finally have parity again between regulatory affairs and the rest of the agency. Until recently, we had only half as many people in field operations as we did in the centers.

PE: What was the ratio historically?

Crawford: When I first got here in 1975, it was half and half. Then, during the Carter administration, there was a cutback of about 1,000 FTEs. Later, there was some more bleeding, and the field took the cuts for a complicated set of reasons. I believe we are getting more even now, and last year's increases have been impressive.

PE: Does that come from the bioterrorism threat?

Crawford: It does, and a lot of it comes from the sheer force of Secretary Thompson, because he picked FDA as something that needed to function fully. His support for the supplemental bio-terrorism legislation got us a big influx of funds and personnel, and that became permanent with the bioterrorism bill.

PE: How would field operations work under a risk management approach?

Crawford: If a product like Lotro-nex (alosetron) enters the marketplace, it comes into the field with a risk-prevention program that is based on risk-assessment. Let's assume that the product is essential to the well-being of 10,000-20,000 Americans. But it must be carefully monitored, and it will take a lot of field time to make sure that takes place. By the time it goes generic, we will have had enough experience with it to know what the risk is and how to manage it.

From the Heart of Texas

Also, contaminants and microbiological concerns must be examined on a risk basis. When I was at USDA's Food Safety and Inspection Service, any chemical in the environment, whether it was cyanide or table salt, was treated the same way. We spent just as much time and got just as much credit for controlling table salt as we did cyanide. Every year we had to go before Congress and explain why we were doing so few inspections of some of those compounds.

So we set up a simple matrix, which is rudimentary for risk assessment. Along the abscissa, we labeled the most toxic compounds A; we labeled the least toxic D. Across the ordinate, there was a numerical system of 1-4 for increasing availability in the environment. If the compound was a D-4, it wasn't very toxic or very available, so why spend time trying to find it? But an A-1 was something that would kill birds in flight, so we had to spend a lot of time on it. We were able to convince Congress and the American people that we shouldn't worry about the Ds or spend much time on the Cs. And, if they cut our budget any more, we would be dealing only with the As, and they would have to accept that.

PE: Traditionally, the field force has been involved with plant inspections and border controls, and CDER [the Center for Drug Evaluation and Research] has been more involved with assessing post-marketing safety issues. Do you see it playing a bigger role in monitoring products once they are on the market?

Crawford: CDER is like the scientific reservoir that gives compliance policy guides to the field. Although Center personnel may go into the field from time to time, that's unusual. The arms and legs of enforcement are in the field. But what to do and how to do it have generally been directed by the Center.

We are building up the field force with more professional school graduates. Its new director is John Taylor, an attorney with a lot of training in biology and toxicology. He worked as senior advisor for regulatory affairs for then-acting commissioner, Michael Friedman, from late 1996 through 1999. If John ever retires, I wouldn't be surprised to see a medical doctor in charge of the field force.

PE: What effect will the shift to risk management have on drug approvals or the ability to prevent, or anticipate, withdrawals?

Crawford: It's no secret that 2-3 percent of the human prescription products we approve are removed from the market later on. That has occurred for at least 25 years in a variety of systems, including the European Union.

But we can't accept it as being a constant. We must keep trying to do better. Through judicious use of risk assessment, as we get experience, we will do a better job. Having a good enforcement and monitoring scheme-in which companies are obligated to report and we are obligated to enforce-will cut down on that. It will never go to zero, but if we could get withdrawals down to less than 2 percent, that would be tremendous.

PE: Would that involve more intense scrutiny of a new therapy during the approval process or demands for more clinical trial data?

Crawford: Not if we can give the industry the right information. We just had a day-long meeting about antibiotic resistance and new industry guidelines for getting antibiotics approved for animal use. The idea is to give clear instructions so pharma companies know what they have to do, so they themselves develop compounds that, though not guaranteed acceptance, are more likely to fit within those guidelines.

Whither the NMEs

PE: Has there been a slowdown in new molecular entities (NMEs) submitted for approval?

Crawford: I just got back from the European Union, and there certainly has been a slowdown there. But we don't know if that's true here in the United States. By the end of the year we should know more.

The European Union visit was alarming for me, because the EU will have only about ten new NMEs this year. That is half of what it has been approving, so something is going on. I've been working with CDER ever since I got back at the end of August to be sure of what is happening in the United States, because we can't approve NMEs if companies don't submit applications for them.

If the number of NMEs presented to us declines, we get blamed by the Wall Street Journal and other organizations for not doing a good job. Although it's not our business to do R&D for companies, it certainly is our business to encourage research and development. Each new generation of drugs put on the market is safer and more effective-that has always been true. So if something interferes with the pharma research process, that would be a great tragedy.

PE: Is there a common theme behind the lack of applications?

Crawford: With gene therapy, some bioengineered drugs, and other products, companies thought that R&D might be the same as it is for chemical entities. But it seems to be taking a little longer. I believe the lag reflects the birth pangs of a new generation of technology that will bring us great advances in medicine. I also think that mergers and acquisitions have had an effect.

Tooling Up


Does risk-based regulation imply a greater trust placed in industry to police itself and, if so, is industry ready for that?

Crawford: We're not relying completely on industry to implement risk-based assessment, because we also will be doing risk assessment and modeling. To be sure, we'll expect companies to be participants in the process. So, to the extent that they are not ready for that kind of prime time, they will need to get ready.

We recognize that no one at FDA, including myself, can define what GMPs [good manufacturing practices] are. But early in FDA's history, we decided that, if we inspected a plant and found it clean with all equipment operating, the product should be safe and effective. Now we know that's not the case if the manufacturing is not state-of-the-art. Our GMP regulations are administered by an archaic system that we have limped along with, and it's gotten too heavy to carry.

The European Union and all other regulatory organizations have either dumped that outdated regulatory approach or are rapidly doing so. So we have to become international leaders in the reform effort. Everybody else is off and running, but they want to see US leadership and to see the best system design we can create. If we develop better GMPs in the estimated two years it will take, that will have a direct impact on improving public health.

I doubt that the new GMP system will look anything like what we have today. It will be a systems approach, with external auditors and a precise, comprehensive set of things to look for and to examine. FDA will need to re-educate the industry, but it must set the standards.

PE: Would it also encourage re-tooling to some extent? Isn't some of this change dependent on modernization or state-of-the-art technology?

Crawford: Yes. If a field investigator filed an inspection report on an outmoded plant and put in all the stats on that plant, the card would pop out saying, "outmoded." This would have serious regulatory consequences.

PE: FDA has cracked down and sent warning letters to major companies that have been around for a long time but have failed to respond. Do you believe that industry is improving?

Crawford: For ten years, we have tried to send the message that manufacturers have to meet GMP standards. Now we are reviewing the warning letters more carefully. There will be fewer of them because we are not sending them out casually. It's a serious matter. When they come, companies must do something, and they are. The industry has clearly gotten the message in the last few months that we won't hesitate to take strong action, and the only way they will get out of the FDA doghouse is to make improvements.

Center Shifts


What is the relationship between risk-based regulation and the moves you've made to shift the review of some products from CBER into CDER?

Crawford: The situation that has led to this change has been going on for a long time. In the early 1980s, the Center for Drugs and the Center for Biologics merged, only to demerge in 1987. One result is that some of the products that CBER approves follow a process that is identical to what CDER does. So why have two different units, both of which must have a critical mass of toxicologists and pharmacologists and manufacturing chemists?

When the two centers merged in the '80s, that was widely perceived as a failure. Therefore, when FDA demerged them, that left a redundancy in operations that no one addressed.

By the time I arrived in February 2002, there was already a committee looking into the issue, two outside consultants had been hired to review the plan, and interviews of the regulated industry and other organizations had taken place. I was asked if I wanted to stop the review along with a lot of other things, and I said no, I wanted to proceed. So in midsummer, I received the recommendation that therapeutic biologics be transferred to CDER's jurisdiction.

PE: That was the committee's recommendation or the consultants'?

Crawford: Both. There was no opposition from any of the parallel review paths. So, I informed CBER leadership of the consolidation decision and gave them a month to rebut it. Then we decided to make the move. Now we have a committee under Mac [Murray] Lumpkin [principal associate commissioner] to put the pieces together and decide who and what will move when.

PE: Are you surprised that there are people at CBER who say, "We had no idea this was happening, and it doesn't make any sense, and it's a terrible idea"?

Crawford: No, I'm not surprised. When you make a management decision like that, you have to be prepared for opposition.

PE: What has been the industry's reaction to it?

Crawford: Several companies have spoken out in favor. I'm not aware that any have spoken out against it.

PE: Not so much publicly, but a lot of industry people are saying, "This isn't what we had in mind. We just wanted to fix CBER." They are particularly concerned about the prospect that it would open the door to generic biologics.

Crawford: We have stated that it would not open that door. We are transferring review authority for certain biologics to CDER, but that does not include new authority for generic products.

PE: Did you get any indication from the Bush Administration about how it felt about the reorganization?

Crawford: No. I was obliged to tell the department, and it had to tell the White House. If they did not like it, they would have let us know. But this is the most facilitating administration I have ever worked for, and I've worked in five. I haven't been second-guessed, and they have treated me as if I was commissioner for eight months. That said, I am very happy that Dr. McClellan is coming. Because, when you take over FDA, you realize that you have a little piece of America in the palm of your hand, and it's counting on you. You can't just say, "I've got every excuse not to make any decisions."

Tactical Retreat


Did you also launch a review of First Amendment issues?

Crawford: I did. What occasioned our review of First Amendment enforcement was that we were losing case after case in court, and most recently in the Supreme Court. Because FDA's record in dealing with the law is so dismal, some people have suggested we consider labeling some products "not approved by FDA" and others "FDA approved." Under that scenario, approved products would cost more and might be safer, and the "not approved" products might cost less. That was a wake-up call, and within ten days we decided to launch a broad review of how we enforce our policies related to communications about regulated products. (See "FDA Demands to be the Final Authority," PE, October 2002, page 33.)

PE: Some say this review of First Amendment enforcement is just a camouflage for FDA to stop regulating communications related to labeling.

Crawford: That's not what it is, but if they feel that way, they should submit a comment to us.

Direct-to-Consumer Conundrum

PE: There seems to be a fairly intense cat-and-mouse game in DTC promotion, in which companies push the envelope and defy FDA to take enforcement action. How do you see the agency dealing with that?

Crawford: Regulating drug advertising is not a precise science. CDER has a fairly efficient system for reviewing DTC promotional materials and deciding if regulatory action is needed. Any recommendation to issue a warning letter goes to the chief counsel, then to me. That does not mean that top officials are limiting enforcement efforts. Often the people at the Center consider something to be perfectly all right, but the attorneys see it differently. So I conclude that judgments about them are highly subjective. We need to refine the process, but, by and large, we've done a good job.

PE: Do you favor DTC advertising?

Crawford: It clearly has gotten people into doctors' offices. It also has opened useful dialogues with physicians. However, FDA's role in regulating it needs to be better defined.

PE: So, would you come down on a manufacturer that said something that you believed was dangerous or could lead to public health problems versus just an infraction of the rules?

Crawford: When we issue a regulation, we must be sure it's legal and will prevail in court if challenged. In the past, we just hoped somebody wouldn't sue. Those days are over. Our attitude now is, if they sue, we want to be able to win.

ailing from a politically well connected Texas family, Mark McClellan likes to quote his grandfather, Page Keeton, as saying, "If you haven't made anybody mad, you haven't done anything." At his confirmation hearing in early October, the nominee for FDA commissioner said he would follow the advice of that law school dean and politician by making decisions that US Senators would not always agree with. He also promised to listen to all viewpoints and to base his decisions on "sound science, careful empirical analysis, and ethical integrity." He concluded by describing FDA as a "great place to make a positive difference in the lives of all Americans."

At age 39, McClellan is one of FDA's youngest commissioners. (See "From the Heart of Texas," page 46.) His strong academic credentials and an ability to sidestep controversy earned him a fairly smooth ride to Senate confirmation.

The key player in accelerating the confirmation process was Senator Edward Kennedy (D, Massachusetts), chairman of the Senate Health, Education, Labor and Pensions Committee. Once Kennedy signaled that he supported McClellan for the job, most of his fellow Senators went along. Although McClellan has strong ties to the Bush administration, he fit Kennedy's criterion of no direct ties to the pharma industry. That McClellan earned his medical degree from Harvard and his PhD in economics from MIT didn't hurt. Only a few lawmakers bothered to show up for the hearing on October 7, deciding, instead, to submit questions for McClellan to answer in writing.

At the hearing, McClellan gave only a few hints of his approaches to dealing with key FDA issues, but he promised to address them more fully once confirmed as commissioner. He pledged to speed up the approval process for new therapies, while also stressing safety concerns. He supported extending user fees to additional products and said that DTC advertising of pharmaceuticals may promote "treatment of conditions that are seriously undertreated." He emphasized that FDA's mission is to ensure that information about regulated products be "truthful and not misleading." One of his top priorities is to stem the flight of professionals from the agency, which is experiencing high turnover.

One question that emerged from the approval process is whether McClellan's strong background in health coverage and benefits issues might increase FDA involvement in that area. As the administration's leading advisor on health policy for the past two years, McClellan has been a central player in efforts to develop a Medicare pharmacy benefit and other issues related to drug coverage by the Health and Human Services Centers for Medicare & Medicaid Services (CMS).

In response to a written question from Kennedy, McClellan said he planned to explore ways for FDA and CMS to improve their "working relationship," which raises the possibility of closer coordination between FDA approvals and CMS coverage. Although McClellan indicated that the two areas are distinct, he noted that the two agencies could collaborate more in safety surveillance of pharma products.

The nominee sidestepped several highly controversial issues, such as abortion policy and the safety of RU-486 (mifepristone). Yet, he revealed some of his attitudes and approaches on other key FDA issues during the hearing and in written answers to questions from Senate committee members. Highlights of his comments follow.

Enforcement Philosophy


Has there been an increase or decrease in FDA enforcement actions since FDA's Office of Chief Counsel began reviewing warning letters before FDA issues them?

McClellan: It is too soon to tell whether there has been an increase in FDA enforcement actions and in referrals to the Department of Justice or an increase in the extent to which letter recipients take corrective actions in response to the warnings. The policy's purpose is to promote a credible, risk-based enforcement strategy. I am committed to ensuring that FDA policies are designed to minimize risks to the public. Under my leadership, FDA will follow up with enforcement actions when companies refuse to follow its regulations.

Q: As commissioner, how will you ensure appropriate, yet consistent, enforcement of FDA rules?

McClellan: I believe in credible, risk-based enforcement. It is my understanding that there were complaints that, in some cases, different districts were taking varying positions on the same issue. There were also complaints that FDA would not follow up on many of the [warning] letters. Moreover, there were assertions that some of the letters were not legally sufficient, and some did not reach the threshold of regulatory significance.

I intend to examine that issue more closely, and, thanks to recent FDA actions, I will have better and more timely data to work with. FDA tracks such letters and has recommitted to the deadlines in its Regulatory Procedures Manual. Between February 27 and September 5, 2002, [the Office of Chief Counsel] reviewed and disposed of 699 letters. It refused to concur in only 6 percent. In fact, on occasion, OCC has urged that the district or center bring an enforcement action instead of sending a letter.

When FDA takes a position, companies must believe that the agency can and will back it up by going to court if necessary. I will work to ensure that FDA takes action when companies fail to comply with warnings.

Generic Drugs & Biologics


Do you believe that abbreviated biologics license applications are inappropriate because they are highly complex, or does the cost and importance of biologic products coming off patent highlight the importance of establishing a generics biologics program?

McClellan: It is true that certain biological products, because of their inherent structural complexity, heterogeneity, and manufacturing process, do not currently lend themselves to being copied generically. The feasibility of interchangeable or generic biologics should be assessed further and rely on scientific knowledge and experience as key factors.

Q: Do you see a need for Congress to amend the Waxman-Hatch Act to reduce the costly legal fights among FDA, brand-name, and generics companies?

McClellan: I fully support the key goals of Waxman-Hatch, including incentives for the research and development needed to create valuable new treatments. The development of many innovative drugs in the past two decades, as well as the shift of almost half of all prescriptions to generic status, is a testament to the importance of that act.

I also appreciate the goals of S. 812 to improve generic competition. As the detailed Federal Trade Commission study of potential abuses of the automatic 30-month stay and other Waxman-Hatch provisions has demonstrated, some provisions may not be functioning as intended. On the other hand, some features of S. 812 go beyond closing the loopholes as recommended by FTC and would potentially delay access to new medications and increase their costs, as a result of much more complex patent filing procedures and new litigation. As commissioner, I look forward to working with Congress to take steps to address these important issues.

Q: When false claims are made about the inferiority of generic drugs, are you prepared to set the record straight?

McClellan: FDA approves generic drugs that are therapeutically equivalent to brand-name drugs. The quality, strength, and purity standards for approval of drugs sold in the United States are uniform, whether they are for generic or brand-name medications. Generic drugs contain the same active ingredients as the brand-name product and are just as safe and effective.

Regulation of DTC Advertising


What action would you take or recommend to assure compliance with existing laws and regulations governing prescription drug promotion?

McClellan: One of FDA's responsibilities is to ensure that the public receives truthful and non-misleading health information on drugs. Section 522 of the bio-terrorism bill will provide additional resources for DDMAC [Division of Drug Marketing, Advertising, and Communications], beginning in fiscal year 2003. If Congress passes appropriations for DDMAC as specified in Section 522, the additional resources will be especially useful for regulation of DTC advertising. Thus, I believe I will have an enhanced ability to help ensure that consumers receive accurate information on drugs.

Public Disclosure

Q: There is concern that FDA's protection of industry trade secrets makes it easy for companies to conceal safety concerns and mislead the public with overly optimistic public statements about a drug's prospects. How would you address that issue?

McClellan: The agency is required by statute and its own regulations to safeguard trade secret and confidential commercial information submitted to it by sponsors of premarket approval applications. It should be possible to both protect trade secrets and take rapid action where there is clear evidence of significant adverse effects. FDA should respond to sponsor concealment of safety information using the full extent of its legal authority.

For products under review that have not been approved, FDA is not charged with policing the marketplace for false or misleading statements. Congress has assigned that responsibility to the Securities and Exchange Commission, which is entitled to initiate enforcement action against a firm for making false or misleading statements or for failing to disclose material information, including material safety information about an investigational new drug.


Q: What will you do to assure that citizens will not be unduly encumbered from obtaining medicines from Canada for their personal use? And what legislative authority might be needed so FDA can make the practice of personal reimportation of prescription drugs acceptable from the perspective of ensuring drug safety and efficacy?

McClellan: From a public health standpoint, importing prescription drugs for personal use is a potentially dangerous practice. Neither FDA nor the American public has any assurance that products from foreign sources are effective or safe or were produced under US good manufacturing practices. Those products may not have been stored under proper conditions or may not be the products that they purport to be. I am wary of subjecting patients to those risks.

My belief is that legislation to provide better prescription drug coverage with more effective price competition in the United States is a much more effective solution to the problem of high prescription drug costs for seniors and others.

Cost & Reimbursement


Given your background in drug cost and reimbursement issues, can you assure that you would oppose efforts to involve FDA in collecting data related to cost, cost-effectiveness, value, and other reimbursement considerations related to the coverage process overseen by HHS' Centers for Medicare and Medicaid Services (CMS)?

McClellan: FDA does not make coverage decisions. Rather, it approves items such as devices and drugs based on their safety and efficacy. Just because an item is safe for marketing, it is not necessarily the most medically appropriate item for a beneficiary, or a good use of taxpayer funds. The activities that you identify relating to cost and reimbursement are not primarily within FDA's mandate.

That said, increased cooperation among federal agencies is wise. I understand that CMS works collaboratively with FDA when gathering and considering evidence to make national coverage decisions. The staffs also collaborate through interagency agreements in setting and enforcing quality standards, quality improvement and measurement activities, and coverage. I will work with CMS Director Tom Scully to explore areas where those two agencies can further improve their working relationship for the benefit of the American public.

FDA Review Process


Since enactment of the Prescription Drug User Fee program, FDA officials have publicly acknowledged the internal pressures on drug review staff to review applications to meet PDUFA's performance goals. As commissioner, what would you do to make sure that FDA scientists and review staff can openly express their opinions on product safety and other important issues?

McClellan: Open discourse within FDA about the safety and efficacy of products under the agency's regulatory authority is essential to decision making about those products. Although I have not yet identified specific new measures designed to promote this principle, I intend to maintain an atmosphere of open dialogue among FDA's employees.

Post-Market Studies


Are you committed to see to it that post-market studies of drugs and biological products are completed and to inform Congress if FDA needs additional authority to enforce those commitments?

McClellan: FDA intends to make information about the status of individual commitments available on its internet site. I understand the importance of this requirement and will work to implement it. I am also aware that Congress instructed FDA to bring forward legislative recommendations regarding post-marketing studies, and I will assess the need to make any such recommendations.

Devices & Combination Products

Q: Will you work to ensure that the President's budget for 2004 includes the additional $15 million authorized in recent user fee legislation for FDA review of medical devices?

McClellan: I plan to work to ensure that the device program receives the funds it needs to adequately implement the program and meet the goals that are laid out in the draft goals letter.

Q: What steps are needed to prepare the agency for dealing with rapidly changing technologies involving medical devices?

McClellan: I support using third parties to supplement the agency's medical device GMP inspections. As with the current third-party review program, adequate protections must be in place, and there must be an opportunity to evaluate the program's success. As FDA gains additional experience with the third-party review program, I believe it would be appropriate to evaluate additional use of outside experts in this area. With adequate procedures in place, the use of such third parties should enhance rather than jeopardize the review process.

Q: Should FDA establish an Office of Combination Products to help deal with those new technologies?

McClellan: FDA has recently taken steps to facilitate the review of combination products within the Office of the Ombudsman. The new program serves as a focal point and advocate for combination product issues. The goal is to develop policies and procedures that facilitate the review of combination products and to monitor the progress of pre-market reviews of combination products. I support these efforts and intend to build on them.

Bioterrorism & Biologics


What safety standards will you implement to ensure that new treatments or vaccines to fight a bioterrorism attack are safe? How do we protect vulnerable, special populations in the event of the unthinkable?

McClellan: As a general matter, FDA cannot license or approve new vaccines or treatments using a "lower safety standard for approval." If a sponsor seeks FDA's approval of a product for use in bioterrorism preparedness by an expedited approval mechanism, such as accelerated approval or the animal efficacy rule, FDA will apply all appropriate safety standards. This rule provides explicit conditions under which studying the effectiveness of products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances can be performed in animals when studies in humans are not ethical or feasible. Those studies can include non-adult animals to provide effectiveness and dose selection data for children.

Q: Are there actions FDA could take to alleviate existing shortages and to prevent future shortages of childhood vaccines?

McClellan: In the future, as in the past, FDA will work with manufacturers to anticipate shortages, to encourage increased production of needed vaccines when shortages are anticipated, and to expedite FDA review of any pending applications or submission for vaccines in short supply.

Currently, there is no mechanism for FDA to get reliable reports from vaccine manufacturers regarding projected shortfalls in production or a decision to stop manufacturing or distributing a vaccine. Advance notification to FDA by vaccine manufacturers would facilitate timely and effective agency actions. For now, FDA must rely on information voluntarily provided by vaccine manufacturers to help mitigate any shortages.

Q: One recommendation to help increase the pipeline of new vaccines is to have FDA review vaccines under its "fast track" or "priority review" authorities. Is that something you would consider?

McClellan: FDA has reviewed, and will continue to review, license applications for vaccines in the most expeditious manner possible. Often, shortages are temporary and are over before even the most expeditious review can be completed. In such cases, the formal designation for the review process has little impact on the shortage.

Thus, as a practical matter, it will be infrequent that a new vaccine will become licensed expressly, and in time, to alleviate a shortage. However, FDA will consider fast-track and priority review designations whenever it appears that FDA can facilitate increased supply of a vaccine through such actions. I also intend to examine the factors responsible for vaccine shortages to determine if further steps may be possible to prevent shortages in the first place.

Q: What action can FDA take to further ensure the safety of blood, tissue, and organ supplies?

McClellan: FDA continues to work with the tissue industry and the Centers for Disease Control and Prevention to provide guidance on procedures to minimize the chance for cross-contamination of tissues with pathogenic organisms during processing. The agency intends to work with the medical community to enhance the sharing of information concerning potentially contaminated tissues and to provide guidance on the submission of INDs [investigational new drugs] for new cellular and tissue-based products.

CBER-CDER Consolidation


If the planned transfer of therapeutic review from CBER to CDER encourages medical officers and scientists to leave FDA, will that seriously risk delay in biologic product reviews?

McClellan: We value the reviewers and plan to assure that the transfer of review locations does not minimize their importance to FDA. By transferring the review of certain biologics applications from CBER to CDER, we will have a larger pool of people capable of conducting reviews. This, coupled with the opportunity for CBER reviewers to work more efficiently on the critical programs remaining within CBER, should help to minimize the concerns suggested by your question.

Research & Labeling


What will you do to ensure that FDA fights to implement the pediatric rule and to defend the rule in court?

McClellan: On April 19, 2002, the department strongly reiterated a commitment to further ensure the safety and effectiveness of drugs used to treat children, including continuation of the pediatric rule. As commissioner, I will continue to enforce FDA's rule requiring companies to take steps to ensure that drugs are properly labeled for pediatric use based on scientific studies. FDA has sought public comment on how best to implement the Best Pharmaceuticals for Children Act and what additional steps, if any, need to be taken to ensure that drugs in children are adequately studied. I share the commitment to ensuring that FDA uses all of its statutory authorities to improve our understanding of the appropriate use of pharmaceuticals in children.

Q: When do you expect FDA to release new pregnancy labeling guidelines?

McClellan: I agree that far too little useful information is available to women and their physicians about the risks of drugs taken during pregnancy. My understanding is that FDA is drafting new regulations on the format and content of the pregnancy and lactation sections of the labeling for prescription medicines. The goal is to publish it within the next 12 months.

We also need to develop a better knowledge base of medication risks during pregnancy. On September 23, 2002, FDA published a final guidance to industry on establishing pregnancy exposure registries to provide clinically relevant human data that can be used in a product's labeling. I will work to build on these efforts to improve the availability of useful information about medication risks during pregnancy.

OTCs & Supplements


What level of emphasis will you place on Rx-to-OTC switches?

McClellan: OTC drugs play an increasingly vital role in America's healthcare systems. As commissioner, my goal is to be proactive in identifying Rx-to-OTC switches of drug products that will provide consumers an enhanced role in their healthcare decisions.

Q: How will you address safety concerns related to some dietary supplements?

McClellan: I will work with the agency and Congress to implement the Dietary Supplement Health and Education Act of 1994 in accordance with Congressional intent. That includes taking steps soon to implement good manufacturing practices for dietary supplement manufacturers. Publishing regulations on GMPs for dietary supplements is an FDA priority. On October 4, 2002, the agency submitted this proposal to the Office of Management and Budget for 90-day review. If confirmed, I will work to implement GMPs for dietary supplement manufacturers as quickly as possible.

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