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As we near the end of the first decade of the 21st century, it is obvious that the discovery, development, and com-mercialization of new medicines is a dynamic process that has become vastly more complicated than it was even a few years ago. It is an international process involv-ing companies located in many different countries, clinical trials performed in even more countries and academic contributions from around the world. There are many hundreds of drugs in clinical development. They are representatives of multiple technologies and chemical classes including small molecules, monoclonal antibodies, other proteins, anti-sense oligonucleotides, aptamers, and gene therapy, and, perhaps in the near future, stem cell-based therapeutics. These clinical trials are sponsored by very large multinational pharmaceuti-cal and biotechnology companies with very substantial experience, generic companies, traditional regional companies expanding toward worldwide markets, and biotechnology companies that range in size and com-petency from very large and experienced to virtual with virtually no experience. The trials are, in fact, often con-ducted by contract research organizations that again vary widely in size, competency, and experience. All of this is managed by a very uneasy collaboration between the industry, academic medicine, and regulatory agencies.

Expectations for the development of new medicines have changed substantially as well. There is greater focus on demonstrating long-term safety. Efficacy trials have become much larger, more complicated and even more multinational. Further, in many therapeutic areas there is increasing demand for long-term outcome studies. These factors contribute to progressively costlier and more time-consuming development cycles that are cou-pled to longer regulatory review processes, more rapid emergence of competitive products and shorter effective

patent lives. These factors, in turn, put more pressure on companies to extract the maximum in sales and profits as rapidly as possible after commercialization, resulting in even greater reliance on direct-to-consumer advertis-ing and efforts to encourage as broad a use of the new medicines as possible.

Contemporaneously, food and food processing, nutritionals, vitamins and supplements, cosmetics, and diagnostic industries have also become much more complex.

In response, the FDA has grown. It has promulgated new rules and guidelines in virtually every area. It has imposed user fees on the industries it regulates and is buffeted by conflicting demands to facilitate the devel-opment of new products, yet reduce risk to unachievable levels. The net result is that no one is satisfied. Patients and patient advocacy groups quite correctly complain about limited progress. The industries contend that the regulatory processes are intrusive, cumbersome, and are applied capriciously. The FDA is criticized consistently and it has been difficult for the agency to recruit and retain outstanding individuals.

In contrast to the dynamic changes recorded by all the regulated industries, science and medicine, the delivery of healthcare, information technologies and media cover-age, the legal basis and charter of the FDA have changed little since the last major overhaul of the legislation in 1962 (1–3). Little wonder then that few, if any, are satisfied with the job that the FDA is doing today. Proposals to institute a systemic overhaul of regulatory processes have been made, but major changes have not been implemented (4).

Despite the fact that there has been no total overhaul of the regulations covering the development of new med-icines, there have been quite a number of new initiatives that are both laudable and establish some of the bases needed for even more significant changes. Most of these

COMMENTARY

Renovation of the new medicine regulatory process

Stanley T. Crooke, MD, PhD

Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA

Address for Correspondence: Stanley T. Crooke, MD, PhD, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA. Tel: (760) 603–2301. Fax: (760) 603–4651. Email: scrooke@isisph.com

(Received 01 July 2011; accepted 19 July 2011)

Clinical Research and Regulatory Affairs, 2011; 28(4): 81–86© 2011 Informa Healthcare USA, Inc.ISSN 1060-1333 print/ISSN 1532-2521 onlineDOI: 10.3109/10601333.2011.607462

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have been summarized in an excellent recent review (5), so I will review them only briefly here. Particularly in the area of cancer chemotherapeutics there have been a num-ber of early approvals based on response rates. However, the experience with gefitinib (Iressa) suggested that early approval based on response rates could result in approv-als of new medicines that are inappropriate (5). Similarly, approvals to commercialize new anti-cancer drugs based on interim analyses of phase 3 data have been granted (6). Thus, there are legal bases for conditional approval in Europe (7) and accelerated approval in the US (8). In some European countries, conditional approval to give access to new medicines for select groups of patients, particularly for life threatening illnesses, is being evalu-ated (5). Additionally, the FDA has recently been granted the authority to limit the distribution of new drugs to limited types of physicians and patients (8) with severe diseases.

Each of these approaches is important and laudable but, I would argue that in the aggregate they have failed to make a significant improvement in the performance of the new medicine development and approval process as a whole. I believe that this is the case for several funda-mental reasons. First, there are equally intense pressures on regulatory agencies to limit risk to unachievable levels. Second, the application of each of these initiatives has been inconsistent and often used only when there was a strong patient advocacy group encouraging more rapid approval. (Are the needs of AIDS patients any more com-pelling than those of other patients with debilitating or life-threatening diseases?) Perhaps more importantly, these initiatives have not been a part of broad changes to assure that the interests of the sponsoring companies, academia, physicians, and patients are as aligned as possible. They have not been integrated into a new approach in which the missions of the regulatory agencies are more clearly defined. They have not been implemented systematically along with other changes to assure better phase 4 moni-toring and more selective distribution of newly approved new medicines. There has been no program to enhance the quality and morale of regulatory agencies and no pub-lic information program to explain the changes to those affected by the regulation has been mounted.

Based on all this, I think the evidence clearly says that change is needed and not simply another set of Band-Aids or new approaches to incenting the FDA by the next director or new recruits to the FDA. Rather, a fundamental change is required. New laws and new charters that recognize the unique value created by new medicines, the unique challenges involved in develop-ing and commercializing these agents, and the new tools provided by new healthcare delivery processes and information management systems are required. In this commentary, I want to propose a new framework for regulation of the development and commercializa-tion of new medicines.

This proposal responds to a number of concerns about the FDA. Specifically, there are legitimate concerns that

FDA is too large and has much too broad a set of tasks as it attempts to regulate several industries and numerous complex disparate processes. The mission of the FDA with regard to the development and commercializa-tion of new medicines needs to be revised and clarified. Regulatory processes are not well integrated into devel-opment activities. The FDA doesn’t have as clear author-ity to manage product introductions as it should. The responses of the FDA are often seen as inconsistent and capricious, with the most conservative, risk averse per-son in a division often able to delay development inter-minably. The advisory committee system is not working and arcane and unrealistic rules about memberships on such committees often result in non-experts serving on the advisory committees. Recruitment and retention of outstanding scientists and physicians to the FDA has been challenging. Obviously, this list isn’t meant to be all-inclusive. Nor do I expect everyone to agree with this list of concerns. What I hope everyone can agree upon is that it is time for us to do a better job as a society. And that this is not an opportunity for finger-pointing, but rather an opportunity for all the stakeholders in the endeavor to put their heads together and devise a solution that better meets our needs. We can and must improve the processes that we hope will lead to be bet-ter healthcare.

In formulating this proposal, I am also mindful that I am suggesting changes that will force the industry, the regulatory agency, academia, and participating physi-cians and patients to participate in the process differently than they have in the past and to share responsibilities for some activities that have not been shared before.

Basic premises

The prudent, cost-effective development and com-•mercialization of new medicines is in the public interest.New medicine development and commercialization •can and should be effectively regulated.The processes used and challenges faced as new •medicines are developed are unique.The risks encountered during the peri-marketing •period, i.e. the first 5 years after initial launch, are substantial and unique.In many instances, at initial launch, it is prudent to •limit the use of new medicines to defined sub-sets of patients and physicians.It is essential to define monitoring and additional •study requirements before initial launch and to commit to expanded label claims and broader use if required post-launch activities are positive.The launch, promotional and sales activities should •be better defined in the context of the initial label and the initial sub-sets of patients and physicians approved for use of the new medicine.The sponsor company is accountable and must •be free to make the final decisions about what

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medicines are developed and how they should be developed.Regulators are accountable and must make the final •decisions with regard to the regulation of the devel-opment and commercialization of new medicines.Effective regulation can best be achieved when:•

Regulatory processes are integrated into the •development and commercialization processes.Regulators and product developers employ •experts with relevant real life experience.Regulatory • policies are clearly enunciated and dynamic and regulatory practices are consistent with policy guidelines.Regulatory processes are as transparent as •possible.Regulatory goals and the goals of those regulated •are as aligned as possible. (I can imagine no area in which there is a greater opportunity for alignment of goals than the need to prudently develop new medicines.)

Proposal

Establish the Bureau of New MedicinesI propose the formation of a new ministry, preferably at the cabinet level, to specifically regulate the development and initial commercialization of new medicines. The Bureau of New Medicines could be a division of a federal drug agency or simply transfer responsibility for medi-cines after the peri-marketing period to the existing FDA.

Some may suggest that the last thing needed is another government agency. Others may say that the current FDA has the mandate and the skills to meet the challenges of prudently regulating the development and commercial-ization of new medicines. I disagree and believe a critical examination of recent history supports the need for radi-cal change.

I believe that a new legal basis is essential. The legal basis should state clearly that it is in the public interest to facilitate the prudent development and commercial-ization of new medicines. The regulatory agency should have greater authority to control initial launch activities and the initial physician and patient populations to be exposed to new medicines. The regulatory agency must be incented and have the tools necessary to use post-marketing surveillance methods that exploit the large payor group databases. The regulatory agency needs greater authority to influence development plans from the inception of clinical trials to the completion of the peri-marketing period. Equally importantly, the regula-tory agency must accept the responsibility to facilitate the prudent development of new medicines that improve health. The regulatory agency must accept that it is dif-ficult to assemble sufficient disease-expert talent into a single agency, and thus find a more effective means of using extramural consultants. The agency must also accept accountability for assuring that the development of new medicines isn’t delayed inappropriately and

that guidelines for development of various types of new medicines are established and followed by the industry and the agency.

I believe a new agency is needed to provide focus and to create a smaller more effective regulatory orga-nization focused on new medicines. Of course, generic medicines, foods, vitamins, additives, and cosmetics have much in common with new medicines. However, the shear scope of the responsibilities of the current FDA requires that it be very large and that the atten-tion of its leaders be divided and driven by one crisis after another. More importantly, no area has the poten-tial to bring more benefit or do more harm than new medicines. By creating an agency based on rational legislation, focused on new medicines, committed to evidence-based decision-making and medicine, and that is relatively small and exploits extramural advisors, we have the best opportunity to facilitate advances in treatment while reducing risk to the maximum extent, consistent with the needs of patients.

I believe the new agency needs to be relatively small and elite. This can be achieved by focusing on only one task—the prudent development and commercializa-tion of new medicines, and by more effective use of clinical and other consultants. I believe that appropri-ate pay structures and bonus systems can help recruit outstanding talent to such an agency, but great talent will be retained only if the agency is well managed, has a clear mandate, clear objectives, and is protected from undue political influences. In the end, critically impor-tant, enormously complex risk/benefit decisions must be made. It only makes sense to recruit and motivate truly outstanding people and give them the tools they need to do their jobs. This can best be achieved by an indepen-dent, focused, relatively small agency.

Scope of activities of the Bureau of New MedicinesThe Bureau of New Medicines will oversee and regu-•late the development of the new medicines from IND submission to initial regulatory approval.The Bureau of New Medicines will define the:•

Initial label.•Sub-sets of physicians who can prescribe the new •medicines.Sub-sets of patients to whom new medicines can •be prescribed.The initial phase 4 monitoring and study plans, •including outcome studies.Paths to expanded uses and potential broader •labels.

The Bureau of New Medicines will transfer the •responsibilities for long-term regulation of medi-cines after completion of required phase 4 activities or 5 years after initial launch.The Bureau of New Medicines will be responsible for:•

Auditing of clinical trials of new medicines.•Initial plant inspections.•All activities necessary to grant initial approval.•

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The Bureau of New Medicines will be responsible for •working with companies developing new drug dis-covery technologies and drugs based on those tech-nologies to ensure prudent cost-effective evaluation and development of these new tech nologies.

MissionsThe missions of the Bureau of New Medicines are to:• Facilitate the prudent cost-effective development of

new medicines.Assure the initial label is appropriate.•Assure that the initial commercialization and pro-•motion are directed to the appropriate physicians and patients.Assure that post-marketing surveillance and phase •4 studies are appropriate and completed in a timely fashion.Facilitate the evaluation and development of new •drug discovery technologies.Assure that new information technologies and •approaches to post-marketing surveillance are developed.Promulgation of evergreened best practice guidelines •for development activities.

ProcessesOrganizationThe Bureau of New Medicines should remain relatively small by focusing strictly on new medicines and employ-ing outside experts.

LeadershipThe leadership should be comprised of those experienced in the development and regulation of new medicines.

Outside consultantsExtensive use of outside consultants to assure that •recent relevant experience is brought to bear on activities in each therapeutic area. Stipends for con-sultants will be paid out of use fees.Outstanding consultants are • encouraged to partici-pate in the clinical trials of drugs in which they are interested.

IND filingIND filing will remain essentially as it is today.

Phase 2 plansAt the initiation of phase 2, companies will submit a summary of phase 2 evaluation plans. The company and representative of the Bureau of New Medicines will agree on the plan.

ExpertsAt the beginning of phase 2 trials, two experts •will be selected, one by the company, one by the Bureau. These experts are to work with the company and the agency throughout the development and

initial commercialization process. They are to pro-vide supervision and guidance with regard to devel-opment issues and plans.The experts will write a brief report to be appended to •the annual report of activities of the IND. They will be expected to participate in regulatory meetings and to deal with any emergent situations. Experts will be encouraged to participate in clinical trials of the new medicine, but will receive compensation for their services strictly from the agency.

Initiation of Phase 3 evaluation working groupsThe sponsoring company will propose initiation of •phase 3 activities, by submitting a phase 2 report and a preliminary phase 3 plan. The opinions of the two experts assigned to the new medicine will be included.The Bureau of New Medicines will have 3 months to •review the proposal and to suggest modifications to the plan.At the initiation of a phase 3 program for a new medi-•cine, a working group will be formed.The Phase 3 Working Group will consist of:•

The experts appointed at phase 2;•An appropriate monitor from the Bureau of New •Medicines;Project leader and medical monitor from the •sponsoring company;Toxicologic representatives from the company •and from the Bureau;Patient advocate;•Two statisticians, one appointed by the company •and one by the Bureau;Regulatory representative from the company; and•Bureau clinical liaison person.•

Responsibilities:•Phase 3 Plan.•

The Phase 3 Working Group will be responsible for working with the company, the Bureau and any drug safety monitoring boards for specific studies to assure that the phase 3 program is completed expeditiously and that any issues that emerge are well managed.

NDA submissionThe sponsoring company will be responsible for prepar-ing and submitting the NDA which will include:

A summary basis for approval;•An initial label;•Initial physician and patient populations to be intro-•duced to the new medicine;An initial marketing and promotion plan;•A phase 4 study plan including potential long-term •outcome studies;A post-marketing surveillance plan; and•A pharmaeconomic analysis based on projected •pricing provided by the sponsoring company.

The sponsoring company will provide all the relevant information to the phase 3 working group and work

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collaboratively with the working group as the company prepares the NDA. The phase 3 working group will write a report that is submitted with the NDA. It is expected that in most cases the report from the phase 3 working group will support the conclusions and proposals made by the sponsoring company in the NDA. In the event that there are disagreements between the sponsor and the working group, these will by highlighted. In the event that there are dissenting views in the working group that cannot be reconciled, these will also be highlighted.

NDA reviewThe submission of an NDA by the sponsoring com-•pany that includes a supportive report by the phase 3 working group will be assumed to be valid.The bureau will have 6 months in which it can pro-•pose alternatives. Any alternatives to approval, initial label, physician and patient populations to be targeted, or other elements of the NDA must be justified.In the event that the sponsoring company and the •phase 3 working group have significantly different opinions, the Bureau will have 9 months to reach its conclusion.If the sponsoring company, the phase 3 working •group and the Bureau can not reach agreement within 3 months after the Bureau issues its report, the bureau will appoint a special panel to reach a final resolution. The panel will be constituted with mem-bers selected by the sponsoring company, the Phase 3 Working Group and the Bureau.

Post-approval monitoringThe Bureau will be responsible for monitoring the launch of the new medicine. From time-to-time based on the completion of new studies, additional clinical experi-ence, and other information, the phase 3 working group will propose new labeling and changes to the promotion plans as well as targeted physician and patient groups. The Bureau will have 3 months to review such submis-sions. In this sense, the process would be quite similar to the staggered approval process discussed earlier.

The management of new medicines after approval will be enhanced by greater utilization of pharmacovigilance programs and healthcare databases.

Product withdrawal or reduced accessRare or idiosyncratic adverse events can not typically be predicted or identified in even large phase 3 programs. Moreover, if outcome studies are completed during phase 4, it is inevitable that some drugs that seem valu-able based on results other than long-term outcome studies will be proven to be of less value (or values) only in a smaller sub-set of patients. The Bureau must have the authority to deal with such findings promptly by forcing the withdrawal of the new medicine, suspension of sales till new trials are completed, or narrowing the patient population to be treated. Some will argue that such

actions may result in a loss of confidence by the public in the new medicine approval process. I do not think that a loss of confidence is inevitable if the new processes are explained well, the access to new medicines is limited to appropriate groups of patients and physicians, marketing and promotion are similarly limited, and the entire pro-cess is as transparent as possible. Quite the contrary, an active process in which all parties are seen to be working toward prudent access to new medicines will enhance understanding of the risks inherent in taking medicines and the process that results in those new medicines being commercialized.

Transfer to the FDAAt the completion of initial phase 4 studies or 5 years after the initial launch, the NDA will transfer to the FDA.

Conflicts of interest

Some will argue that the use of outside consultants as extensively as I propose is unwise and could lead to con-flicts of interest. I would argue that the need for greater expertise and a real knowledge about the patients being treated are the most essential components in effective regulation and that it simply is impossible to recruit all the talent needed to a regulatory agency. Perhaps of more concern may be the concept of identifying ‘experts’ who will work as consultants to the agency and will help the company devise appropriate development plans, then participate in the approval phase. I do recognize that this could lead to both the perception and perhaps the reality of conflict of interest. Nevertheless, I think the continuity of expert advice is so critical to good develop-ment and regulation of new medicines, that it is essential that an expert consultant system be adopted. Obviously, appropriate disclosure policies and auditing processes will have to be implemented, but conflicts of interest are inherent in all regulatory processes and should be manageable.

I also propose a much closer partnership between the companies developing drugs, academic investiga-tors, and the regulatory agency—again, there will be concern about conflicts of interest. There will also be concern in the industry about adding more authority to the agency and consultants. I think the benefits should outweigh the risks if true integration of regulation, development, distribution, and commercialization can be achieved.

Conclusions

In this commentary, I have proposed a radical solution to the challenges of regulating the development and com-mercialization of new medicines. The core elements of the proposal are:

Creation of a new agency to facilitate the prudent •cost-effective development and initial commercial-ization of new medicines.

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New authority for the agency to define appropriate •sub-sets of physicians and patients to which a new medicine may be marketed.Much more extensive use of therapeutic experts who •will help guide the development of new medicines.A Phase 3 Working Group that will work with spon-•soring companies to present an approvable applica-tion to the agency.The requirement that the applications be approved •or if modifications are requested by the agency, the requirement the agency justify its position.A means of rapid adjudication of differences of opin-•ion between the agency, the sponsor, and the Phase 3 Working Group.Much more emphasis on phase 4 follow-up studies •and monitoring.

I certainly recognize how substantial the changes I am proposing are. The notion is to integrate regulatory processes with development activities to facilitate the development of new medicines. I would suggest that the Bureau of New Medicines assign highest priorities to first in class agents designed to meet important unmet medical needs and agents that are representative of new technologies.

I also understand that I am suggesting that sponsor-ing companies and the regulatory agency, physician, and patients share full control of activities that have tradition-ally been theirs alone. However, I think the improvements in the quality of development, the efficiency of the process, and the control of the overall activities make this proposal attractive. I believe if implemented appropriately this proposal would eliminate the apparent capriciousness of the current process and better assure that these complex risk-benefit judgments are made by the most experienced minds working dispassionately toward shared goals.

My hope would be that, if adopted, this proposal would result in value to all constituents.

Consistently better risk to benefit judgments.•More efficient development of new medicines that •bring benefit.A more predictable and manageable development •and regulatory process for the businesses involved.A better focused, less politicized regulatory effort •that will support the recruitment and retention of more outstanding individuals to our key regulatory agency.

More transparency throughout the process, and there-•fore more true access and input by all constituencies, including patients and patient advocacy groups.

Obviously, what I have proposed is only an outline and much work would be required to draft legislation and guidelines that would make the concepts workable. Moreover, I fully recognize that there may be better solu-tions that may be proposed. What is important to me, and should be important to all humans, is that we begin a constructive dialog that will lead to a more effective pro-cess that does a better job of balancing risks and rewards and meeting the needs of patients.

Acknowledgements

Thank you to C. Frank Bennett, PhD, Richard S. Geary, PhD, and B. Lynne Parshall, JD, for their helpful comments.

Declaration of interest

The author is employed at Isis Pharmaceuticals.

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