FOOD AND DRUG LAW JOURNAL Analyzing the Laws, Regulations, and Policies Affecting FDA-Regulated Products

Transcription

1 FOOD AND DRUG LAW JOURNAL Analyzing the Laws, Regulations, and Policies Affecting FDA-Regulated Products The Web of Clinical Trial Registration Obligations: Have Foreign Clinical Trials Been Caught? Carolyne R. Hathaway John R. Manthei J. Ben Haas Elizabeth D. Meltzer FDLI VOLUME 64 NUMBER

2 2009 CLINICAL TRIAL REGISTRATION OBLIGATIONS 261 The Web of Clinical Trial Registration Obligations: Have Foreign Clinical Trials Been Caught? CAROLYNE R. HATHAWAY * JOHN R. MANTHEI ** J. BEN HAAS *** ELIZABETH D. MELTZER **** I. INTRODUCTION The web of overlapping requirements, standards, recommendations and policies governing the conduct of clinical trials highlights the intense scrutiny of the ethical, data quality and public access issues raised by human trials that are conducted to demonstrate the safety and efficacy of medical products marketed in the United States. One relatively recent development is the requirement that sponsors register and make public information about their clinical trials and clinical trial results. These clinical trial registration requirements illustrate the interests of patients, providers and researchers in increased visibility, transparency and accessibility of clinical trials and the data they generate. These requirements, however, pose regulatory, logistical, and practical hurdles for companies sponsoring clinical trials of drugs and medical devices. The registration of clinical trials and clinical trial results is governed by federal and state law, 1 administrative policies and industry groups that mandate or encourage registration as a condition of membership. The specific registration requirements may vary and apply differently depending on the type of trial, making it difficult for sponsors and investigators to determine whether their trials are triggered. Further, if sponsors and investigators do find their trials trigger the registration requirements, it is often difficult to identify the specific requirements and obligations that apply. These difficulties have been particularly acute for sponsors conducting trials outside of the United States, which may ultimately be used to support U.S. regulatory approval. Given the novelty, complexity and ambiguity of the registration requirements, the demands that registration imposes, and the importance of generating acceptable data to support the Food and Drug Administration (FDA) approval, the various potentially-applicable requirements and their application to foreign trials warrant closer analysis. Part II of this article discusses the legal framework governing the registration of clinical trials originally established by the Food and Drug Administration Modernization Act 2 (FDAMA) and recently expanded by the Food and Drug Administration Amendments Act of (FDAAA). * Ms. Hathaway is a Partner in the law firm of Latham & Watkins LLP, Washington, DC. ** Mr. Manthei is a Partner in the law firm of Latham & Watkins LLP, Washington, DC. *** Mr. Haas is an Associate in the law firm of Latham & Watkins LLP, Washington, DC. **** Ms. Meltzer received her J.D. from Georgetown University Law Center, M.P.H. from Johns Hopkins Bloomberg School of Public Health, and A.B. from Georgetown University. 1 See Part II.B.6, infra, for a discussion of the preemption of state registration requirements imposed by federal law. 2 FDAMA, Pub. L. No , 111 Stat (1997)(amending the Federal Food, Drug and Cosmetic Act (FDCA), 21 U.S.C. 301 et seq., and the Public Health Service Act (PHSA), 42 U.S.C. 201 et seq.) (codified in scattered sections of 21 U.S.C. and amended by FDAAA, H.R. 3580, 110th Cong. (2007) (enacted in Pub. L. No , 121 Stat. 823 (2007)). 3 FDAAA, Pub. L. No , 121 Stat. 823 (2007), (amending 402 of the PHSA, 42 U.S.C. 282, and scattered sections of the FDCA, 21 U.S.C. 301 et seq.). 261

3 262 Food and Drug Law Journal Vol. 64 Part III assesses the potential impact of these federal registration requirements on clinical trials conducted outside of the United States. Although the application of FDAAA to foreign trials is unclear, sponsors and investigators conducting clinical trials outside the United States must consider the potential application of the registration requirements to such trials and the consequences of the failure to comply with those obligations. Part IV addresses additional sources of clinical trial requirements imposed by professional and industry groups which may be pertinent to sponsors of foreign clinical trials. These include the policies of the International Committee of Medical Journal Editors (ICMJE) which preclude or restrict publication of manuscripts that do not comply with its registration requirements, and the Pharmaceutical Research and Manufacturers of America (PhRMA) policy encouraging its members to register and publish clinical trial information. These overlapping registration requirements create a complicated maze for those sponsors and investigators who may be unfamiliar with the U.S. regulatory requirements. Accordingly, this article is intended to inform these parties of the various sources of requirements, and explain how failure to comply could affect their path to U.S. marketing approval. II. LEGAL FRAMEWORK GOVERNING THE REGISTRATION OF CLINICAL TRIALS A. The Beginning of the Federal Registry: FDAMA Since 1997, federal law has required the registration of qualifying clinical trials in a publicly accessible databank. 4 Section 113 of FDAMA established a databank, available at ClinicalTrials.gov, for the registration of, and public access to, information about clinical trials conducted by both public and private sponsors. 5 Although the term clinical trials is quite broad, and includes any research study in human volunteers to answer specific health questions, 6 not all clinical trials triggered FDAMA s registration requirement. The law applied only to those clinical trials of drugs, including biological drug products, that tested 1) the effectiveness of experimental treatments for 2) serious or life-threatening diseases or conditions under 3) FDA s Investigational New Drug (IND) regulations. 7 Thus, FDAMA limited the application of the registration requirement in three important ways: First, FDAMA s registration requirement applied only to clinical trials intended to study the effectiveness of an experimental drug. It did not apply to trials of medical devices. Moreover, according to FDA, only Phase II and III drug trials with efficacy endpoints met this criterion. 8 The main purpose of Phase II and III 4 Pub. L. No , 111 Stat Note that although FDAMA established the registration requirement in 1997, the first clinical trial was not made available online until See FDA, Food and Drug Administration Modernization Act (FDAMA) section 113 and ClinicalTrials.gov, fda.gov/oashi/clinicaltrials/section113/. 5 Pub. L. No , 111 Stat FDA, Basic Questions and Answers about Clinical Trials, FDA s IND regulations define the term clinical investigation more narrowly, as any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. 21 C.F.R Pub. L. No , 111 Stat FDA, Guidance for Industry: Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions at 5 (2002), available at PDF.

4 2009 CLINICAL TRIAL REGISTRATION OBLIGATIONS 263 trials is to study how effective the drug is in humans. 9 In contrast, Phase I drug trials, designed to test the metabolism and pharmacologic actions of the drug [and] side effects, 10 were not subject to FDAMA s registration requirement since they are not designed to test efficacy. Second, FDAMA s registration requirement applied to studies of drugs intended to treat a serious or life-threatening disease or condition. According to FDA, a disease or condition is life-threatening if either 1) death would be highly likely unless the course of the disease or condition were interrupted, or 2) the outcome of the disease or condition would be potentially fatal, and the endpoint of interest in the trial is survival. 11 Whether a disease is serious, however, is a matter of judgment based on a number of factors, including survival, day-to-day functioning, and the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one. 12 FDA s guidance identifies HIV, Alzheimer s, heart failure and cancer as examples of serious diseases and recognizes that many other chronic illnesses may lead to serious outcomes in certain circumstances. 13 Third, FDAMA s registration requirements applied to trials conducted under FDA s IND regulations. 14 Drug trials that were not conducted under an IND, either because the study did not involve a new, unapproved drug or use or because the study was conducted outside of the United States, were not within the scope of FDAMA s registration requirement. Finally, FDAMA left open the possibility for an exemption from the registration requirement. 15 These criteria limited FDAMA s registration requirement to only a subset of ongoing clinical drug trials those testing potential treatments for serious or lifethreatening diseases, under FDA oversight pursuant to an IND. For such trials, FDAMA required clinical investigators to submit four specific types of information for inclusion in the databank, including: 1) descriptive information, 16 2) recruitment information, 17 3) location and contact information, 18 and 4) administrative information. 19 FDAMA did not, however, require that that clinical trial results 9 21 C.F.R (c) FDA, Information Program on Clinical Trials, supra note 8, at 4-5 (citing the definitions in 21 C.F.R (a) (2002)). 12 at Clinical trials conducted under Treatment INDs, and Group C protocols, for particular cancer drugs, were deemed to automatically meet all qualifying criteria and had to be reported to the databank. 15 Trial information was exempted from registration under FDAMA if the trial sponsor provided a detailed certification to the Secretary of the Department of Health and Human Services (HHS) that disclosure of such information would substantially interfere with the timely enrollment of clinical trial subjects, and the Secretary did not disagree. 42 U.S.C. 282(j)(4) (subsequently amended by Pub. L. No , 121 Stat. 823 (2007)). If the Secretary disagreed, the Secretary would provide the sponsor a detailed written determination that such disclosure would not substantially interfere with enrollment, and the exemption would not be granted. 16 Descriptive information includes: a brief title (in lay language); a brief summary (in lay language); the study design, study phase and study type; the condition or disease under study; and the intervention. FDA, Information Program on Clinical Trials, supra note 8, at Recruitment information includes: information on the status of the study (i.e., whether the study is still recruiting individuals for participation) and the status of a particular site, as well as eligibility criteria such as gender and age. 18 Location and contact information includes: the location of the trial and the contact person to whom inquiries about enrollment should be directed. 19 Administrative data includes: a unique protocol ID number, information about the study sponsor, and the verification date. In addition, FDA requests inclusion of the IND number to verify the existence of, and link the study to, FDA s IND, but this information will not be made public.

5 264 Food and Drug Law Journal Vol. 64 be reported to, or included in, the database. The required information had to be provided to the databank within 21 days after opening enrollment in the trial, 20 and the public generally had access to such information within two to five days after submission. 21 Although FDAMA s mandate was intended to improve public access to clinical trial information, it was limited in the scope of its application and the information it required. In addition, FDAMA lacked enforcement provisions which limited its effectiveness. 22 The Agency s lack of enforcement authority contributed to less-than-perfect rates of compliance. 23 In 2007, Congress considered proposals to address this enforcement concern. These proposals substantially modified and expanded the registration requirement, and led to a compromise bill that became law in September B. The Expansion of the Registry: FDAAA In 2007, the U.S. House of Representatives and the U.S. Senate each introduced separate legislation to expand the scope and the force of FDAMA s clinical trial registration requirement. 24 A compromise bill, H.R. 3580, 25 was passed by both houses and signed into law in September This law, called FDAAA, substantially expands and extends the pre-existing clinical trial registration requirements. Specifically, FDAAA 1) extends the application of the registration requirement to a greater number of clinical trials, including, for example, certain medical device trials; 2) expands the nature of information required to be submitted; 3) requires the submission of clinical trial results, and specifies new timelines for submission and new exemption criteria; 4) adds a certification requirement; 5) imposes penalties for noncompliance; and 6) provides other modifications to strengthen the preexisting registration framework under FDAMA. 1. Applicable Clinical Trials By broadly defining the term applicable clinical trials, FDAAA extends the universe of clinical trials subject to the registration requirement. FDAAA defines applicable clinical trials to include all applicable device clinical trial[s] and applicable drug clinical trial[s]. An applicable device clinical trial is 1) a prospective clinical study of health outcomes; 2) comparing an intervention with a device subject to section 510(k), 515, or 520(m) of the FDCA; 3) against a control in human subjects (other than feasibility studies). Applicable drug clinical trials are post-phase I drug studies subject to section 505 of the FDCA or section 351 of the U.S.C. 282(i)(3) (2006) (subsequently amended by Pub. L. No , 121 Stat. 823 (2007)); see also FDA, Information Program on Clinical Trials, supra note 8, at 4 (explaining that FDAMA reads not later than 21 days after the approval of the protocol, which the agency has interpreted to mean within 21 days after the trial is open for enrollment, since FDA does not approve protocols). 21 FDA, Information Program on Clinical Trials, supra note 8, at See Evans, J. Tori, Clinical Trial Data Bank: The Missing Link in the Dissemination of Information to the Medical Community, 9 QUINNIPIAC HEALTH L.J. 69, (2005). 23 A 2006 study conducted by FDA to assess compliance with 113 of FDAMA showed that approximately 3 out of 4 qualifying clinical cancer trials complied with the registration requirements. FDA, FDAMA 113: Analysis of Cancer Trials Submitted May July 2005 (June 2006), fda.gov/oashi/clinicaltrials/section113/2005statusreport/. 24 S. 1082, 110th Cong. (2007); H.R. 2900, 110th Cong. (2007). 25 FDAAA, supra note 2. 26

6 2009 CLINICAL TRIAL REGISTRATION OBLIGATIONS 265 PHSA, which govern the use of a drug or biologic prior to marketing and following approval. 27 These definitions represent a major expansion in the scope and types of trials subject to the registration requirement. Significantly, FDAAA extends the registration requirements to include certain clinical trials on medical devices, which had been excluded entirely from the scope of FDAMA, potentially imposing significant new obligations on medical device manufacturers and those responsible for the study. In addition, unlike FDAMA, FDAAA does not limit the application of the registration requirements to studies of drugs to treat serious or life threatening conditions or to trials conducted pursuant to an IND. By defining an applicable drug trial to include trials subject to the new drug approval requirements of section 505 of the FDCA, FDAAA potentially extends the registration requirements to non-ind studies that are later submitted to FDA, for example, to support an NDA. 28 FDA has not confirmed this interpretation, but the definitions of applicable drug and device clinical trials are sufficiently broad and ambiguous to potentially encompass many drug and device studies not previously subject to registration under FDAMA. 29 On December 8, 2008, a draft guidance document was issued, and later modified on March 9, 2009, to address the lack of clarity of the definitions of applicable clinical trials. 30 The document suggests that an applicable clinical trial must have a nexus to the United States. For example, the notice provides that a non-u.s. drug or device trial may be an applicable clinical trial if the drug or device under study is manufactured in the United States. 31 The draft notice also states that the term applicable drug clinical trial may include non-u.s. drug trials that are conducted under an IND. The guidance does not, however, indicate whether the term applicable device clinical trials includes device trials conducted abroad under an investigational device exemption 32 (IDE). It is not clear from the notice whether this distinction between non-u.s. drug and device trials is intentional. Although the draft guidance provides some additional elaboration regarding the application of the statutory definitions, it leaves many questions unanswered and does not provide definitive boundaries on the scope of these terms. Significantly, the application of the registration requirements to foreign trials that are subsequently used in furtherance of U.S. marketing submissions remains unclear. 2. Expanded Informational Requirements FDAAA also expands significantly the clinical trial information that was required to be reported under FDAMA. FDAAA requires the submission of more detailed U.S.C. 282(j)(1)(A)(iii). The term drug is defined in the law as a drug as defined in section 321(g) of this title or a biological product as defined in section 262 of Title (j)(1)(A)(vii). All references to drugs throughout this article encompass biological products, as well. 28 This interpretation is certainly plausible given FDA s commentary that the reference to 505 of the FDCA was simply a streamlined reference to all applications and submissions possible under section 505 of the [FDCA]. Agency Information Collecting Activities, 73 Fed. Reg. 50,024, 50,026 (Aug. 25, 2008). One such submission under 505 is an NDA that references non-ind studies. 29 See Part III, infra. 30 Draft Elaboration of Definitions, at 5-7 (2009), available at ElaborationsOnDefinitions.pdf. This draft is posted on a webpage maintained by the National Library of Medicine at the National Institutes of Health (NIH). It is unclear whether authorship is shared by both FDA and NIH An IDE permits the use of an investigational device in clinical trials to collect data sufficient to support an application for marketing approval. See 21 C.F.R. pt. 812.

7 266 Food and Drug Law Journal Vol. 64 information in the four categories established under FDAMA. For example, with respect to descriptive information, FDAAA requires 1) a brief title and summary of the trial intended for the lay public; 2) the primary purpose of the study; 3) the study design; 4) the study phase and type; 5) the primary disease or condition being studied; 6) the intervention name and type; 7) the study start date; 8) the expected completion date; 9) the target number of subjects; and 10) the outcomes, including primary and secondary outcome measures. 33 FDAAA also requires more detailed information regarding recruitment, study location and contacts, and administrative data. 34 In addition, the law authorizes the Secretary of HHS to further expand these informational requirements by regulation. Under FDAAA, responsible parties for the trial must submit the required information within 21 days after the first patient is enrolled. 35 Information with respect to drug clinical trials will be posted within 30 days of submission. 36 But for trials on uncleared or unapproved devices, information is withheld from publication until 30 days after clearance or approval is achieved. 37 If the device under study was previously cleared or approved, publication may be withheld until 30 days after information about the clinical trial s results are due to be posted Clinical Trial Results FDAAA requires that results of those trials involving drugs or devices that have been cleared or approved by FDA be reported to the database. 39 The law directs the Secretary of HHS to expand the existing ClinicalTrials.gov databank to include clinical trial results, make those results publicly available, post a glossary for the lay public explaining technical terms, and provide information to assist the public in interpreting the results properly. 40 Once an applicable clinical trial of a cleared or approved drug or device is completed, FDAAA requires the following information to be submitted to the registry: 1) the demographic and baseline characteristics of the patient sample, 2) the primary and secondary outcomes, 3) the point of contact, and 4) whether there are any agreements between the sponsor and the principal investigator restricting the discussion of results. 41 In addition, the Secretary must add links to FDA documentation about the trial, Medline citations to publications regarding the trial and the entry for the drug in the product label databank. 42 FDAAA also requires the Secretary to promulgate regulations requiring the submission of adverse event information by March 2009, 43 or default rules for reporting serious and frequent adverse event will go into effect in September U.S.C. 282(j)(2)(A)(ii)(I) (j)(2)(A)(ii)(II)-(IV) (j)(2)(C) (j)(2)(D)(i) (j)(2)(D)(ii)(I) (j)(2)(D)(ii) (j)(3)(E)(ii) (j)(3)(B) (j)(3)(C)(i)-(iv) (j)(3)(A)(ii)(I)-(II). 43 Although a technical corrections bill passed the House to add the word devices to FDAAA s requirement that the FDA issue regulations for including specific adverse events from trials in the clinical trial registry within 18 months of the Act s enactment, the bill did not pass the Senate. Consequently, the provision on adverse events appears to only cover applicable drug clinical trials U.S.C.. 282(j)(3)(I).

8 2009 CLINICAL TRIAL REGISTRATION OBLIGATIONS 267 In general, the Secretary has broad discretion to require the submission of other categories of results information, 45 as well as to determine what additional information might be required. For example, the Secretary must promulgate rules for responsible parties to report supplementary results data, 46 and must decide whether results information will be required for clinical trials testing products that are not approved or cleared. 47 The timeline for submission of results information varies depending upon the nature of the study. Generally, the responsible party must submit results within one year of the earlier of the estimated completion date or the end date of the trial. 48 The Secretary, however, can increase this timeline by up to 18 months. 49 Responsible parties must, therefore, carefully estimate the completion date in order to avoid triggering registration obligations before the trial is completed. For trials of a drug or device seeking initial approval, licensure, or clearance, the responsible party is not required to submit results information until 30 days after the product receives approval, licensure, or clearance. 50 The law is silent with respect to the submission of results information if a drug or device is not ultimately approved or cleared. Results information on trials testing new uses for previously approved, licensed, or cleared drugs or devices must be submitted within the earlier of: 1) 30 days after approval licensure, or clearance; 2) 30 days after issuance of a non-approval, non-licensure, or non-clearance letter; or 3) withdrawal of a marketing application after 210 days without resubmission. 51 Finally, FDAAA permits extensions for submission of results data on a showing of good cause. The Secretary may waive the submission of certain results information if (s)he decides that extraordinary circumstances justify the waiver and that providing the waiver would be in the interest of public health or national security Certification Requirement Another important addition under FDAAA is the law s new certification requirement. Under FDAAA, regulatory submissions to FDA must be accompanied by a certification that all applicable requirements of the clinical trials registry have been met. 53 Recognizing that imposing the certification requirement on all regulatory submissions would not serve the purpose of the clinical trials registry because not all regulatory submissions include information that is intended to be posted on the registry, and other submissions may incorporate information that has already been provided in a previous certification, FDA issued a guidance document which provides a list of regulatory submissions that need not be accompanied by a certification. 54 Although FDA s guidance limits the scope of the certification requirement, (j)(3)(D)(iii)(IV) (j)(3)(D)(iii) (j)(3)(D)(ii)(II) (j)(3)(E)(i) (j)(3)(D)(iv)(I) (j)(3)(E)(iv) (j)(3)(E)(v) (j)(3)(H) (j)(5)(B). 54 FDA, Draft Guidance for Sponsors, Industry, Researchers, Investigators, and Food and Drug Administration Staff Certifications to Accompany Drug, Biological Product, and Device Applications/Submissions: Compliance with Section 402(j) of the Public Health Service Act, Added by Title VIII of the Food and Drug Administration Amendments Act of 2007 (2008), available at gov/ohrms/dockets/98fr/fda-2008-d-0224-gdl.pdf.

9 268 Food and Drug Law Journal Vol. 64 the requirement imposes a significant obligation on those conducting clinical trials, and the failure to certify or a false certification could result in administrative delays and potential penalties. 5. Enforcement Authority Perhaps the most important change to FDAMA introduced by FDAAA is its authorization of penalties for noncompliance. FDAAA makes it a violation to: 1) fail to submit required information; 2) fail to submit a certification of compliance where required; 3) submit a false certification of compliance; or 4) submit false or misleading information to the registry. 55 Penalties for these violations may include a civil monetary penalty of up to $10,000 for all violations adjudicated in a single proceeding, 56 which may increase to $10,000 per day for violations continuing 30 days after the responsible party has received notice of the violation and failed to correct it. 57 Additionally, FDAAA directs the Director of the NIH to publicly announce any violations of the registration requirement on the registry, creating a source of public reprimand for companies conducting such trials. 58 Finally, applicable clinical trials funded by government agencies including FDA, NIH and the Agency for Healthcare Research and Quality (AHRQ) are subject to verification of compliance with the registration requirement before any remaining or future grant money is released. 6. Miscellaneous Provisions of FDAAA FDAAA includes a number of additional provisions intended to strengthen the clinical trial registry requirements. For instance, the law allows those responsible for clinical trials that do not fall within the qualifying criteria to submit information about such clinical trials voluntarily. 59 Additionally, the law makes clear that clinical trial submissions must be updated at least once a year, unless there are no changes to the information. 60 Finally, the law specifically preempts state or local requirements for the registration of clinical trials information. 61 Effective December 27, 2010, individual state requirements for the registration of clinical trials will no longer be legally enforceable. Taken together, the changes implemented by FDAAA strengthen and extend the clinical trial registry requirements established under FDAMA. These provisions were enacted to improve public visibility of, and accessibility to, clinical trials and, through increased enforcement and oversight, to expand the number of trials and the amount of information regarding those trials that is made available to the public. Nonetheless, uncertainty remains regarding FDAAA s application to certain trials, particularly those conducted abroad. The following section explores the application of FDAAA s registration regime to such trials U.S.C. 331(jj)(1)-(3) (f)(3)(A) (f)(3)(B) U.S.C. 282(j)(5)(E) (j)(4)(A); see Part IV, infra, discussing the relevance of the voluntary submission provision of FDAAA for the clinical trials registration requirements of the ICMJE U.S.C. 282(j)(4)(C) (noting, however, that if the recruitment status changes or the trial is completed, that information must be updated for publication in the databank within thirty days of the change) note.

10 2009 CLINICAL TRIAL REGISTRATION OBLIGATIONS 269 III. APPLICATION TO FOREIGN CLINICAL TRIALS FDAAA substantially expands the registration requirements that were imposed by FDAMA and increases the potential risks and consequences of non-compliance. Nonetheless, many of the details regarding the application and implementation of the new requirements remain unresolved. In particular, questions remain regarding the extent to which FDAAA applies to studies conducted outside of the United States. As discussed in Part II.B, the definition of applicable clinical trials is limited to those trials of drugs and devices subject to FDA regulatory requirements. The December 8, 2008 draft elaboration attempted to clarify the application of the term applicable clinical trials to studies conducted outside of the United States. The draft guidance suggests that to be an applicable clinical trial, a foreign trial must have a U.S. nexus. According to the draft guidance, foreign trials of products manufactured in the United States or any of its territories have a U.S. nexus and may therefore be deemed applicable clinical trials subject to the registration requirements. A foreign drug trial that is conducted under an IND may also fall within FDAAA s registration requirements. The notice does not address whether the term applicable device clinical trials includes device trials conducted abroad under an IDE, and it is not clear whether this distinction between non-u.s. drug and device trials is intentional. An argument can be made, however, that an IDE provides an adequate nexus to bring the trial within the scope of FDAAA. Nonetheless, according to FDA, non-u.s. trials involving products that are not manufactured in the United States or any of its territories, and drug studies that are not conducted under an IND, lack a U.S. nexus and are outside of the of the reach of the U.S. regulatory regime. The draft elaboration does not, however, address the status of a foreign trial that, at the time it was conducted, had no U.S. nexus, but that is subsequently used to support an application for clearance or approval. One interpretation is that such trials become subject to FDA regulatory requirements at the time an application for U.S. marketing approval is submitted, thus falling within the definition of applicable clinical trials and triggering the registration and certification requirements of FDAAA. This result is theoretically consistent with the purpose of the clinical trial registry to increase the transparency of clinical trials and clinical trial results for products marketed in the United States. The guidance, however, simply does not address the situation where a foreign trial that is not conducted under an IND or an IDE and uses products that are not manufactured in the United States subsequently becomes subject to FDA s regulatory requirements at the point that the trial is used for the purpose of marketing the product in the United States, thus triggering FDAAA s registration and certifications obligations. Whether foreign studies not conducted under FDA regulations become applicable clinical trials when a U.S. nexus arises raises a number of important theoretical and practical issues. FDA appears to be of the view that, once an applicable clinical trial, always an applicable clinical trial. There is no indication, however, that the agency takes the converse position, that once a trial is determined not to be an applicable clinical trial, it remains as such for the lifetime of the trial and beyond. Moreover, if such trials become applicable clinical trials at the time they are used to support a U.S. marketing application, it is not clear how the responsible

11 270 Food and Drug Law Journal Vol. 64 parties for such non-u.s. trials are to meet their registration obligations. Many of FDAAA s requirements and timelines require the registration of information while the trial is ongoing, raising questions as to whether, when, and how a foreign study that becomes subject to the registration requirements only after the trial is complete can realistically comply with those requirements. For example, descriptive information, recruitment information, location and contact information, and administrative data must be provided to the databank within 21 days of the first patient s enrollment. A study that becomes subject to the registration requirements only after it has been completed cannot comply with this timeline unless the study s sponsor or principal investigator anticipated that the trial would subsequently be used to support a U.S. marketing application and complied with FDAAA s provision permitting voluntary submissions. Such an interpretation would impose a significant burden on companies conducting clinical trials overseas who may not have the foresight or regulatory sophistication to comply with FDAAA well ahead of any U.S. contact. Alternatively, FDA could adopt an approach by which the only obligations that attach for a foreign study not conducted under an IND or IDE, using products not manufactured in the United States, are those that are realistically feasible at the time the study becomes an applicable clinical trial. In this case, those obligations that would have attached earlier in the trial s life-cycle would no longer be applicable. The registration of trial results, though, might be required of such foreign trials, given that compliance with such requirements would still be possible and would conform to the purpose of FDAAA by increasing the transparency of the drug development process. However, given the lack of clarity regarding whether, how, and when FDAAA s registry requirements apply to foreign trials that subsequently become subject to FDA regulation, the responsible parties of trials can only speculate as to their obligations. The application of the certification requirement discussed in Part II.B to foreign trials using products not manufactured in the United States and not conducted under FDA regulations raises additional questions. FDA s draft guidance does not exclude from the certification requirement regulatory submissions that reference such foreign trials. Thus, it appears that the certification requirement applies to submissions that reference 1) U.S.-based trials, 2) non-u.s.-based trials conducted under FDA regulations or using products manufactured in the United States or its territories, and 3) non-u.s.-based trials not conducted under FDA regulations and not using products manufactured in the United States. As such, the certification form would have to be provided for submissions referencing foreign trials, regardless of whether the foreign trial were deemed to be an applicable clinical trial. The Certification of Compliance, Form FDA 3674, 62 provides those making regulatory submissions with three options to indicate their compliance with the registration obligations of FDAAA. The submitter must certify that FDAAA s registration requirements either A) do not apply because the submission has not referenced a clinical trial, B) do not apply because the clinical trial referenced in the submission is not an applicable clinical trial, or C) have been met because the trial referenced in the submission is an applicable clinical trial. Of course, as discussed above, the uncertainty regarding the application of the definition of an applicable clinical trial to certain foreign clinical trials makes it difficult, if not impossible, 62 FDA, Form FDA 3674, Certification of Compliance, under 42 U.S.C. 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. 282(j)), available at opacom/morechoices/fdaforms/fda-3674_508.pdf.

12 2009 CLINICAL TRIAL REGISTRATION OBLIGATIONS 271 for the submitter to determine whether to mark box (B) or box (C). A responsible party that marks the incorrect box may face potential penalties for the failure to submit the required information, the failure to submit the certification form, or the submission of a false certification form. As FDA and NIH continue to interpret and implement the registration requirements of FDAAA, it will be important for sponsors and investigators of foreign trials to consider these issues in connection with their regulatory and clinical trial strategies. IV. ADDITIONAL SOURCES OF CLINICAL TRIAL REGISTRATION REQUIREMENTS A number of independent professional associations and trade groups have joined in the effort to increase visibility of, and accessibility to, information regarding clinical trials and their results. These independent obligations often differ from the registration obligations of FDAAA, complicating compliance for sponsors of trials that meet their qualifying criteria. Both ICMJE and PhRMA have adopted voluntary requirements for clinical trial registration. Compliance with the ICMJE policy constitutes a prerequisite for publication in ICMJE journals, and compliance with the PhRMA policy serves as a precondition for group membership. Although these requirements are not enforced by federal law, the consequences of non-compliance can be substantial for members of the biotechnology industry, for whom membership in trade groups and publication in top journals is necessary for their success. A. The International Committee of Medical Journal Editors Policy The ICMJE establishes criteria for publication of manuscripts and articles in a number of influential, peer-reviewed medical journals. In 2005, the ICMJE established requirements making publication of a study in an ICMJE member journal 63 contingent upon previous registration of the clinical trial in a clinical trial databank. According to ICMJE, clinical decisionmaking often depends on an entire body of research, which may include unsuccessful or negative 64 trials, or even trials that do not provide an answer to the initial hypothesis at all. The ICMJE policy was adopted to address the concern that selective reporting of trials distorts the body of evidence available for clinical decisionmaking, 65 and to ensure that decisionmakers have access to the entire body of evidence and not only to those trials that succeed. The ICMJE policy applies to clinical trials that initiated enrollment after July 1, In the 2005 version of the policy, which was subsequently updated, clinical trials were defined as studies that prospectively assign[] human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 66 Studies designed to measure toxicity of a drug or pharmacokinetics (Phase I trials) were specifically exempt from the registration 63 The ICMJE encourages non-member journals to enforce its policy, which raises the possibility that publication in a non-member journal may require compliance with the ICMJE policy. ICMJE, Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors, at Negative trials are those trials that are deemed less exciting because they show that a new treatment is inferior to standard treatment

13 272 Food and Drug Law Journal Vol. 64 requirement. In July 2008, however, ICMJE adopted a new definition 67 modeled after that of the World Health Organization (WHO). ICMJE now defines a clinical trial as any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. 68 This definition specifically includes Phase I studies that simply test safety and toxicity. Thus, the ICMJE policy captures a larger subset of trials than those for which registration is required under FDAAA. Unlike FDAAA, the ICMJE policy does not designate the ClinicalTrials.gov databank as its databank of choice. Instead, the ICMJE makes clear that it does not advocate one registry over another, and specifies that the trial must be registered in a databank that 1) is free and accessible to the public, 2) is open to all prospective registrants, 3) is managed by a not-for-profit organization, 4) ensures the validity of data, and 5) is electronically searchable. 69 Five clinical trial registries currently meet these criteria, 70 and in 2007, the ICMJE recognized any primary registry participating in the WHO s International Clinical Trial Registry Platform (ICTRP) as acceptable. 71 In contrast to this flexibility regarding where to post information, the ICMJE policy is very firm with respect to the information that must be reported. The minimum required categories of information include: 1) a unique identifying number, 2) a statement of the interventions and comparisons studied, 3) a statement of the study hypothesis, 4) definitions of the primary and secondary outcome measures, 5) eligibility criteria, 6) key trial dates, 7) the target number of subjects, 8) the funding source, and 9) the contact information for the principal investigator. 72 Thus, sponsors and investigators whose trials are not subject to FDAAA s registry requirements may still need to consider registration in a databank if they intend to publish the study in an ICMJE publication. The fact that FDAAA s and the ICMJE s qualifying criteria and informational requirements differ makes compliance with both somewhat complicated. In many instances, the ICMJE registration requirements are more stringent than those imposed by FDAAA. For instance, although FDAAA requires registration within 21 days after enrollment of the first subject in a trial, ICMJE s policy requires registration prior to the first patient being enrolled. Additionally, ICMJE requires submission of Phase I studies, but FDAAA does not. Thus, in determining which trials to register, and when to make those submissions, sponsors and investigators who wish to preserve their publication options should comply with the more stringent registration requirements. In some cases, ICMJE s registration obligations conflict with those of the FDAAA, making compliance with both seemingly impossible. For instance, FDAAA requires that publication of information about ongoing clinical trials of devices that have not yet been cleared or approved be delayed, while ICMJE forbids such a delay. In these circumstances, ICMJE urges sponsors and investigators to register in ClinicalTrials.gov, in compliance with FDAAA, as well as in another registry recognized by ICMJE that does not invoke FDAAA s provision leading to 67 ICMJE, Clinical Trial Registration: Looking Back and Moving Ahead, clin_trial07.pdf. 68 at Statement from the International Committee of Medical Journal Editors, supra note 63, at These five registries include: 1) ClinicalTrials.gov, 2) 3) 4) and 5) ICMJE, ICMJE Frequently Asked Questions: Questions about Clinical Trials Registration, 71 ; see also Clinical Trial Registration: Looking Back and Moving Ahead, supra note Statement from the International Committee of Medical Journal Editors, supra note 63, at 1.

14 2009 CLINICAL TRIAL REGISTRATION OBLIGATIONS 273 delayed posting. 73 Of course, dual registration adds costs, increases the burden, and imposes yet another step in the expanding list of registration obligations. In contrast to FDAAA s requirement to register results, it is ICMJE s policy to withhold the publication of results in a registry, to avoid posting results that have not been subjected to an independent peer-review process. 74 Moreover, ICMJE s acceptance of a study for publication in a member journal is contingent on the study s results not having been previously published elsewhere. To address the concern that submission of results in compliance with FDAAA could compromise publication in an ICMJE member journal, ICMJE clarified its policy stating that results posted in the same primary clinical trials register in which the initial registration resides will not be deemed a previous publication as long as that data is presented in a brief, structured abstract or table of less than 500 words. 75 Sponsors and investigators thus must consider ICMJE s requirements and limitations when submitting results information in compliance with FDAAA. B. The Pharmaceutical Research and Manufacturers of America Policy Industry associations such as PhRMA, a well-recognized professional organization of pharmaceutical and biotechnology companies, have adopted their own clinical trial registration policies. PhRMA requires its members to agree to a voluntary policy for the registration of certain clinical trials. PhRMA s policy has slightly different qualifying criteria than both FDAAA and ICJME and less severe consequences for noncompliance. PhRMA s registration requirement is triggered for 1) ongoing or new hypothesis-testing clinical trials that are conducted on drugs or biologics, 2) that are either marketed or intended for marketing in the United States, 3) irrespective of the disease studied and the location of the trial. This definition provides general, though imperfect, overlap with the qualifying criteria for registration of drug and biologics trials under FDAAA. 76 Notably, though, PhRMA s policy also specifies inclusion of trials conducted outside of the United States where those trials are intended to support a U.S. marketing application. PhRMA directs its members to register their qualifying trials in the ClinicalTrials.gov databank. The policy states that members should abide by the timelines and informational requirements provided in section 113 of FDAMA, 77 and adds a few additional informational requirements. 78 Starting in 2002, well before FDAAA was 73 ICMJE Frequently Asked Questions, supra note 70, at 1. ICMJE also suggests that sponsors and investigators choose not to answer the optional question allowing for delayed posting during the registration process. However, the FDAAA does not appear to permit NIH to make this delay optional specifying that the Director of NIH shall ensure that information for an applicable device clinical trial is posted publicly not earlier than the date of clearance or approval of the device. 42 U.S.C. 282(j)(2)(D)(ii) (emphasis added). 74 ICMJE, Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication, available at 75 ICJME, Basic Results Reporting at ClinicalTrials.gov and Prior Publication, available at 76 Part I.B, supra. PhRMA s policy was implemented before FDAAA was passed. The qualifying criteria for registration under PhRMA s policy were much more expansive than those under then-existing law (FDAMA), which limited the registration requirement to trials of experimental treatments for serious or life-threatening diseases. PhRMA s policy did not limit registration based on disease severity or type, making it progressive. 77 The PhRMA policy has not been updated since the enactment of FDAAA. 78 In addition to the information required by FDAMA, the PhRMA policy requires membersponsors to provide to the databank: trial description in lay terminology, trial phase, trial type, trial status, trial purposes (treatment, diagnosis, prevention, etc.), intervention type (drug, vaccine, etc.), condition or disease studied, inclusion/exclusion criteria (gender, age, etc.), site location and/or contact information. Many of these additional data elements are now required under FDAAA.

15 274 Food and Drug Law Journal Vol. 64 passed, PhRMA s membership policy required the timely communication of the meaningful results of controlled clinical trials of marketed products or investigational products that are approved for marketing, regardless of outcome. 79 Communication initially was permitted through publication in a peer-reviewed medical journal, abstract submission with a poster, oral presentation at a scientific meeting, or publication in some other way. In 2004, PhRMA developed a central results registry at ClinicalStudyResults.org for this communication. PhRMA s requirement to publish clinical trial results differs somewhat from that recently imposed by FDAAA. Under the PhRMA policy, member-sponsors must submit to the online databank: 1) the proprietary and generic names of the drug; 2) a link or reference to the FDA-approved drug label; 3) the study indications; 4) the sponsoring company s name; 5) a bibliography of published studies; and 6) a standardized summary of unpublished studies including information about study center, design of trial, number of patients studied, dose and mode of administration, and summary of conclusions and outcomes. 80 In addition, because clinical trial results are located in a separate databank, sponsors must cross-reference the clinical trial in the results databank with the corresponding unique identifier provided by ClinicalTrials. gov. 81 Sponsors must register results within one year of trial completion if the trial is completed after FDA approval. Exceptions to this deadline are available however, if publication in a peer-reviewed journal would be compromised, or if publication would violate some other law. 82 PhRMA s policy has not yet been updated since the enactment of FDAAA, which now mandates the publication of clinical trial results. Thus, it is unclear how compliance with FDAAA and publication on ClinicalTrials. gov will affect PhRMA s registration and publication policy. Although the PhRMA policy does not specify the consequences for failure to register a trial, industry support of clinical trial registration has probably led to the substantial increase in compliance with the federal clinical trial registration requirements seen over the past few years. For example, within a month after the ICMJE policy went into effect in 2005, the pre-existing ClinicalTrials.gov registry jumped from 13,153 to 22,714 trial registrations. 83 By April 2007, there were over 40,000 trials registered. 84 These spikes in registration may reflect not only an increased awareness of the federal requirements, but also the support and industry-imposed requirements of organizations like ICMJE and PhRMA. V. CONCLUSION The overlapping web of registration requirements, standards, recommendations, and policies forms a complex and comprehensive clinical trial registration framework that has expanded the availability of clinical trial information, increased the visibility and transparency of trials, and facilitated greater public access to, and participation in, such trials. At the same time, however, these requirements have erected new hurdles and imposed additional burdens for companies conducting clinical trials. The lack of clarity regarding the scope and application of these obligations and their implications for non-u.s. clinical trials complicates matters further. The consequences of non-compliance with these requirements can 79 See PhRMA, PhRMA Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results, Clinical Trial Registration: Looking Back and Moving Ahead, supra note