Statement to the United States Congress and Food and Drug Administration Regarding Rare Disease Clinical Trials, Access to Therapeutic Products and Selected Regulatory Policy Recommendations

August 29th, 2003

Written By: Les Sheaffer, National MPS Society Board of Directors, Chairman – Committee on Federal Legislation and Sissi Langford, National MPS Society Board of Directors, Co-Chair Committee on Federal Legislation


The National MPS Society is a 501c3 Non Profit organization representing Mucopolysaccharidosis (MPS) and Mucolipidosis (ML) children and families in the United States. The Society’s mission is to pursue cures for MPS and ML disorders, provide family support and promote public and professional awareness of MPS disorders. The Society funds small research grants, advocates and participates in enhancing and supporting sound public health policy and federal biomedical research activities, collaborates with the scientific community, hosts annual national family and scientific conferences and conducts national and local fundraising activities. The Society is governed by an elected Board of Directors and employs 2 professional staff members.

The FDA’s commitment to public health and safety through evaluation of drugs, biologics and medical devices for safety and efficacy is a significant component in the continuing enhancement of what is the world’s premier health care structure here in the United States. Our concerns are not with the FDA’s commitment to ensure that only safe and effective therapeutics are available to the American public, but rather that the application of certain regulatory policies in the pursuit of these goals may lead to delays in accessing beneficial therapeutic products.

With the April 30th 2003 FDA approval of Aldurazyme to treat MPS I, the National MPS Society has developed this document to publicly state our views and recommendations with respect to the FDA’s approach to orphan disease therapeutics. This document was developed in consultation with a diverse body of professionals familiar with these important issues and represents the culmination of MPS Society views and supported recommendations.

We hope this document will facilitate a meaningful dialog with Congress and the FDA on how we may work together to enhance access to critically important rare disease therapies.

Specific Issues of Interest

The National MPS Society wishes to comment on the role of the FDA in the development of treatments for rare diseases such as MPS. Specifically, the Society is interested in clarifying the scientific and practical rationale for the use of surrogate endpoints in developing treatments for MPS and the legislative and legal basis for the use of surrogate endpoints in the FDA approval process. The Society is interested in promoting fast track approval policy and clarification with respect to the ability of the FDA to approve new products/treatments based on a single clinical trial as outlined inFDA Modernization Act of 1997 (FDAMA). Finally, the Society has an interest in further enhancement of these provisions as outlined in the most recent reauthorization of thePrescription Drug User Fee Act (PDUFA) (Specifically Section 502 (3)(B)(ii) and (iii) of HR.3448)as well as composition and functioning of FDA Advisory Committees and use of independent consultants.

Overview of the FDA Modernization Act of 1997 (FDAMA)

The purpose of this legislation, which amended the Federal Food, Drug and Cosmetic Act relating to the regulation of food, drugs, devices and biological products, was to enhance the FDA’s mission due to changes in technology, trade and public health complexities.

Important provisions include User Fees for applications and goals that reduce the average time required for a drug review. The fees are used to reform managerial issues and to hire additional staff to the agency’s drug and biologics program. The act also includes new initiatives designed to streamline the application process for drugs and biological manufacturing changes, accelerated review of important new medications, to increase patient access to experimental drugs and medical devices and expanded databases for clinical trials. The act deletes the prohibition on the dissemination of information by manufactures about unapproved off label uses of drugs and medical devices. The act also reinforces measures to prevent potential unreasonable risk of illness and injury from medical devices and issued changes to the food safety and labeling requirements. Finally, this act simplifies many regulatory obligations of manufacturers and codified that one clinical study can form the basis for product approval.

Supporting Information and Rationale for MPS Society Recommendations

In the interest of tying past history to current policy and our recommendations, it should be noted that Enzyme Replacement clinical trials are currently underway for MPS II, VI. Additionally, enzyme is being developed for MPS VII.

Historical Background of Approval Process of Aldurazyme for Treatment of MPS I

MPS I is a lysosomal storage disease caused by a deficiency of the enzyme alpha-L-iduronidase. It is a progressive, debilitating and fatal genetic disease for which no specific drug treatments existed prior to Aldurazyme.

December 1997: The enzyme replacement therapy with recombinant human alpha-L-iduronidase for MPS I that would eventually be known as Aldurazyme (laronidase) was developed by Dr Emil Kakkis at UCLA and a human clinical trial was initiated after FDA review.

September 1998: BioMarin Pharmaceutical, Inc. and Genzyme Corporation formed a joint venture to develop and commercialize Aldurazyme. The drug companies obtained Orphan Drug designation for Aldurazyme for MPS I from the FDA and orphan medicinal product designation from the EMDA (Endocrinologic Medicines Evaluation Agency)

January 2001: The results of the first clinical trial of Aldurazyme were published in the New England Journal of Medicine. Ten patients with MPS I received Aldurazyme intravenously once a week for 52 weeks. Improvement was seen in organomegaly and urinary glycosaminoglycan levels (surrogate markers) and in joint range-of-motion and sleep apnea (clinical endpoints).

November 2001: BioMarin and Genzyme announced positive findings from the Phase 3 clinical trial of Aldurazyme. This trial included forty five patients in a randomized, double-blind, placebo-controlled study designed to evaluate the safety and effectiveness of Aldurazyme in patients with MPS I. Patients treated with Aldurazyme demonstrated an improvement in pulmonary function and in walking ability. Improvements were also seen in urinary glycosaminoglycan levels. The most common reported reactions were fever, headache, rhinitis and rash.

July 2002: The U.S. Patent and Trademark Office issued a patent covering Aldurazyme.

September 2002: FDA accepted for review the complete final portion of the “rolling” Biologics License Application (BLA) from BioMarin and Genzyme. This includes a formal request for Priority Review, an FDA procedure generally reserved for products that address an unmet medical need. Under PDUFA 3 Priority Review status specifies that the FDA will respond to the filing within six months from the date of filing.

January 2003: The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously that Aldurazyme had shown efficacy in treating MPS I, without serious safety concerns. In two separate votes the panel voted 12 to 0 that the Phase 3 trial showed a meaningful treatment effect in both primary endpoints ? pulmonary capacity, as measured by percent predicted forced vital capacity; and endurance, as measured by the distance covered in a six-minute walk test.

April 30, 2003: Aldurazyme received final FDA approval for MPS I patients with ongoing clinical trial commitments

We are interested in exploring fast track approval options for these enzyme replacement therapies. A detailed look at Aldurazyme’s approval process will contribute to illustrating how this may be accomplished.

In our view, under more aggressive circumstances the FDA could have approved this product based on the changes in the surrogate endpoints in one clinical trial, with additional phase IV requirements. Our concern is that based upon the information we have, the requirement of a second trial may have delayed approval for several years. In the end, the second trial confirmed the results of the first trial validating that the surrogate (urinary GAG) was predictive of clinical benefit.

Additional depth and perspective of the importance of these issues and improvements in policy as well as the opportunity to make positive change is further supported by the interest of the National Institutes of Health, clinical investigators, bench researchers, academia, the Congress and the FDA itself. The following are selected items that serve as additional indicators that the serious and expeditious consideration of these issues and recommendations are justified and timely.

On January 18, 2001 the NIH opened a Program Announcement (PA-01-043) titled”Biomarkers and Clinical Endpoints in Pediatric Clinical Trials”. The purpose of this program was to support ancillary mechanistic studies of diseases pathogenesis and results of therapeutic interventions as well as determination of biomarkers or surrogate endpoints and validation of clinical endpoints in infants and older children. The mechanism remains open until January of 2004.

On January 13 through 15, 2003, in a meeting of the FDAEndocrinologic and Metabolic Drugs Advisory Committee, the committee expressed support for the approval of Aldurazyme (ERT for MPS I approved April 30th, 2003) and Fabryzyme (ERT for Fabry Disease approved April 23, 2003). The panel of independent experts appointed by the FDA clearly stated their support for the FDA employing regulatory procedures currently available for the licensure of therapeutic products for these types of rare diseases, In addition, Advisory Committee members expressed support for the use of surrogate endpoints in clinical trials for these disorder groups.

On February 27, 2003, the NIH opened an Request for Applications (RFA) titled”Rare Diseases Clinical Research Network”(RR-03-008). One of the stated purposes of this RFA includes longitudinal studies of individuals, phase one and two clinical trials and pilot projects with rare diseases. The Research Objective language included the development of Biomarkers as a focus of these Rare Disease Centers. In our view it is logical to assume that if the NIH is investing in the development of Biomarkers, the recognition and acceptance of these markers in trials by FDA should follow.

On April 23, 2003, Fabrazyme was approved using the accelerated approval procedure based upon its effect on a surrogate endpoint. FDA Commissioner Mark McClellan said -“This priority approval of an orphan drug illustrates the FDA’s commitment to approving innovative new therapies for patients with serious life threatening diseases quickly, based upon response to treatment of biological markers likely to predict long term benefit” and “The orphan drugs program provides crucial incentives for innovators to develop new treatments for rare diseases. By approving this new biotechnology therapy under the ‘accelerated approval’ process, we are making this product available more quickly to patients who need it”In June 2003 FDA Commissioner McClellan announced that-FDA would attempt to reduce the review cycle by an additional 10% to allow more rapid accesses to treatments.The National MPS Society applauds Commissioner McClellan for his forward thinking perspective and support of these approaches.

On May 8 and 9, 2003 the Office of Rare Diseases (NIH), American College of Human Genetics Foundation, Office of Orphan Drug Development (FDA), Department of Health and Human Services and Society for Inherited Metabolic Disorders hosted a workshop titled”Ultra Orphan Genetic Disease Therapeutics: Surrogate Markers and Related Issues”This conference brought together representatives from the FDA, NIH, industry, patient organizations, medical professionals and the affected community to examine the issues of surrogate endpoints, regulatory and legal issues, promotion of research and development of rare diseases therapies, data gathering and analysis and case studies.

We have spoken to conference participants who indicated consensus was reached that the FDA has statutory authority to implement the enhancements supported by the National MPS Society. The general tone of the May 8th, 2003 meeting was supportive of further examination and improvement with respect to the use of surrogate markers and related issues.

General Regulatory Policy Recommendations of the National MPS Society Inc.

The issue of how to address and implement sound and appropriate rare disease clinical trials policies, including surrogate endpoints and biomarkers is not new. However, it is an issue that in our view and that of many within the rare diseases community believe should be addressed at this pivotal point in time.

The statutory means to further improve the speed of approval and availability of treatments for rare disorders already exist in theFDAMAandPDUFA, and we encourage FDA and Congress to pursue the opportunity to do so, and offer the following recommendations:

A. “Fast Track” expedited review of orphan products and “Priority Review” policy

Fast Track review policy (Section 112 FDAMA) has been useful in improving communication between industry and the FDA, shortening review cycles and allowing license applications to be submitted in sections contributing to reducing the length of review periods and approvals. The application of clarified first cycle review guidelines under PDUFA 3 (Section X HHS PDUFA Reauthorization Performance Goals and Procedures) should provide additional improvement in review efficiency.

We are gratified by the FDA’s use of fast track and recommend this policy continue to be aggressively employed in the review of rare disease products. We recommend all reasonable efforts be made to ensure that the efficiency of priority first cycle review be enhanced as per PDUFA 3 to ensure swift evaluation of rare disease therapeutics.

B. Codification of Accelerated Approval Regulations to expedite new treatments for life threatening and severe diseases

FDAMA codified Accelerated Approval regulations that had been in use for many years (Section 112 FDAMA). Most significant to the rare disease community is the component that allows approval of a license application based upon effect on an endpoint other than survival or irreversible morbidity. This is an extremely important policy, as the use of surrogate endpoints is essential to the rapid development of new treatments for rare diseases.

It should be noted that the use of surrogate markers in rare disease clinical trials is quite significant in light of the reality that many disorders like MPS and other lysosomal storage disorders are progressive in nature and in some cases certain “clinical” changes or benefits that cannot be measured in the timeframe of a trial due to the slow response of certain tissues such as bones. In our view efficacy should include the slowing or stopping of further degeneration not simply reversing disease.

In many rare disorders, the biology of the disease is often well understood. It is reasonable to assume that the FDA could, and in our view should, apply a more flexible approach to considering surrogate endpoints as acceptable markers when evaluating efficacy for rare disease therapies. The overwhelming majority of these disorders have no other effective means of treatment and many, including MPS disorders, are fatal. Clearly the use of surrogate endpoints should be acceptable in demonstrating efficacy in clinical trials for rare disorders, especially in fatal and severely disabling rare disorders where alternative treatment options do not exist. Clinical confirmatory data can be collected in a post approval setting.

We are very encouraged by Mark McClelland’s comments regarding the use of surrogate endpoints and the potential for biomarkers to accelerate the drug development process. We are also encouraged by his apparent willingness to embrace new statistical approaches that may facilitate the conduct of the clinical verification studies. We do however believe FDA needs to focus on developing appropriate study designs that can be employed for clinical verification studies. The design of these studies is a critical component for rare diseases that have no other treatment options available. The gold standard of randomized, placebo controlled, post approval studies in our view are neither ethical nor feasible for rare diseases.

We very strongly recommend that the FDA aggressively implement the acceptance of surrogate endpoints in developing proof of efficacy in rare disease clinical trials. This step will contribute significantly to the availability of therapies for thousands of children and adults who currently have no treatment options available to them. In addition, enhanced focus is needed with respect to developing appropriate, feasible clinical verification studies so that accelerated approval regulations can be applied to rare disorders.

C. Confirmation of the FDA’s ability to approve products based upon a single clinical trial 

FDA license requirements have historically required “substantial evidence” of efficacy. FDAMA included language that further defined the requirements of “substantial evidence” (Section 115 FDAMA). The language specifically states that a”single and well controlled” clinical trial with “confirmatory evidence” is acceptable for licensure, including pre approved clinical studies, post approval studies and other scientific data. The language further states that the FDA may approve new products on the basis of a single clinical trial with appropriate supportive information. In our view the FDA’s 1998 definition of “adequate and well controlled” may be overly restrictive, and is certainly too restrictive for rare diseases to meet.

We strongly recommend the FDA aggressively pursue the use of single trial models and employment of registry information gathering in a post approval setting when evaluating the approval of therapies for fatal and debilitating rare disorders. In addition with respect to collection of information and confirmatory evidence, we suggest the use of data collected in a post approval setting through database registries. A number of registries exist for lysosomal storage disorders including MPS I that contain a wealth of very significant information. In our view consideration should be given to the use of these registries as model mechanisms for collection of information in the post approval setting.

General Policy Recommendations not Related to FDAMA Supported by the National MPS Society Inc.

To enhance the development of trial design through the use of consultants and improvements in composition, function, efficiency and effectiveness of the FDA’s Advisory Committees and we suggest the following recommendations:

A. Enhancement of FDA Advisory Committees and Use of Independent Consultants

We recommend that the FDA establish and convene Advisory Committees early in the development process in order to allow experts to participate in both clinical trial design pre IND and pre Phase 3 clinical trial as well as in final review committee meetings. Additionally, we support the appointment of 2 full time or ad hock geneticists to the Endocrinologic and Metabolic Drugs Advisory Committee with the appropriate depth of experience with respect to lysosomal storage and similar disorders.

With respect to independent consultants, we recommend the FDA utilize qualified independent consultants as per the draft guidance document issued by the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research regarding (CDER) “Independent Consultants for Biotechnology Clinical Trial Protocols” on 5-12-2003. We believe the implementation of policy utilizing independent consultants in identifying appropriate surrogate endpoints will result in trials that are less cumbersome for both FDA and industry, thereby improving efficiency and ultimately availability of lifesaving therapeutics.

Closing Comments

The National MPS Society, along with many in the rare disease community, believe that we are at a pivotal time in the history of rare disease therapies.

Congress has made unprecedented investments in rare disease research with the passage of theRare Diseases Act of 2002and theRare Diseases Orphan Drug Product Development Act of 2002. In addition, Congress doubled the budget of the National Institutes of Health increasing support of biomedical research overall. The result of the passage of theOrphan Drug Act of 1983and implementation of theFDA’s Orphan Drug Programhas been the approval of 240 products benefiting the rare disease community. We believe this success can be expanded with enhanced application of sound regulatory policy.

Clearly the time to examine these issues is at hand. Therefore, we respectfully request the United States Congress and the Food and Drug Administration to carefully and thoughtfully consider the information shared here and seek the swift application of the recommendations contained in this document as per existing FDAMA policies. Furthermore we encourage Congress to work to ensure the FDA has all the resources needed to efficiently and effectively perform its critically important mandate. In doing so, together we can further improve the quality of life for Americans with rare diseases and provide a tangible future for children with these disorders.

Respectfully Yours,

Ernie Dummann
Chair, Committee on Federal Legislation
National MPS Society Inc.
PO Box 14686
Durham, NC27709
Phone: 919-806-0101
Fax: 919-806-2055

Informational Sources used in the Development of this Document

Genzyme Corporation Website
BioMarin Website
Food and Drug Administration
Library of Congress
NIH Office of Rare Diseases National MPS Society Publications
United States Congress
National Institutes of Health Website
Robert Desnick, MD, PhD, Mt.Sinai
Scientific Advisory Board of the National MPS Society