Articles Posted in Clinical Trials

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Congress passed the Food and Drug Administration Amendments Act of 2007 (“FDAAA”) to give the U.S. Food and Drug Administration (“FDA”) new authority to regulate the safety of marketed drugs. As part of this authority, FDA may require drug companies to propose and implement Risk Evaluation and Mitigation Strategy (“REMS”) for certain drugs whose risk- benefit profiles warrant safety measures beyond professional labeling. FDA may require REMS as part of the approval of a new drug or biologic (brand or generic), or for an approved product when new safety information arises. If FDA determines that a drug has been shown to be effective but is associated with an adverse drug experience, the FDA will require that the REMS have elements to assure safe use (“ETASU”). An example of an ETASU is that health care providers who prescribe the drug have particular training or experience or are specially certified.

The FDA, Federal Trade Commission, and generic drug manufacturers have raised concerns that branded drug manufacturers could be using REMS to impede generic competition. One concern is that branded companies may use REMS distribution restrictions to deny generic companies the drug samples they need to conduct necessary testing and otherwise meet the requirements for generic drug approval. Another concern is that branded drug firm may abuse situations where FDA approval of a generic drug is conditioned on the utilization of a single, shared ETASU by both the generic and branded companies. Essentially, the concern is that branded firms are impeding negotiations of a single, shared ETASU in order to delay generic entry.

To address these concerns, the Senate Judiciary Committee introduced Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act of 2016 on June 14, 2016. The bill—co- sponsored by Senators Grassley (R-IA), Klobuchar (D-MN), Leahy (D-VT), and Lee (R-UT)— permits a generic manufacturer to sue the branded manufacturer if: (1) the branded manufacturer fails to “provide sufficient quantities of [a drug sample] on commercially reasonable, market- based terms”; or (2) branded and generic manufacturers are unable to develop single, shared ETASU after 120 days of initiating a request to develop a shared ETASU. The relief contemplated in the bill is (1) a court order that the brand company provide the drug sample or the brand and generic develop single, shared ETASU or generic firm join a pre-existing ETASU; and (2) monetary award.

AMAHQChicago.pngOn January 22, 2014, the Journal of the American Medical Association (“JAMA”) took a closer look at the FDA approval process for drugs and medical devices. On the surface these studies were designed to characterize the type of pivotal data relied on by FDA for approval (or denial) of new drugs and devices. The conclusions from these studies and some of the associated “Opinion” articles suggest, however, that the editors of JAMA, and perhaps its members, believe that FDA should make physicians and patients more acutely aware of the information relied on for new approvals, as well as side effects observed following approval.

The main article, entitled “Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012“, took as a starting point that physicians and patients do not understand or have the tools to evaluate the different strengths of clinical evidence used by FDA to approve new drug and device therapies. Based on an Internet-based study, for example, the study reported that a national sample of 4316 adults (68% response rate) found that 39% believe FDA approves only “extremely effective” drugs and 25% only drugs without adverse events, which the authors said may reflect the opinions of some physicians.

Taking a closer look at these approvals, the authors concluded:

Our characterization of pivotal efficacy trials . . . demonstrates that the quality of clinical data evidence used by FDA to make approval decisions varied widely across indications. Although the vast majority of indications were supported by at least 1 randomized, double-blinded trial, there was wide variation in trials’ choice of comparators and end points, duration, size, and completion rate. In addition just more than one-third of indications were approved on the basis of a single pivotal efficacy trial.

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electronicclinicaldata.jpgOn October 28-29, 2013, Q1 Productions hosted a conference on Clinical Data Management Innovation. On October 29, 2013, FLH’s Brian J. Malkin and Julie Kurzrok presented an “Update on FDA’s Draft Guidance for Electronic Source Data in Clinical Investigations”. The two-day Conference featured a look at innovative strategies and technologies affecting forward-thinking companies involved in clinical studies and clinical data management. The Conference included topics of interest to clinical data managers (“CDMs”) as well as individuals who supervise or support CDMs to better understand the evaluation and selection of new technologies to meet FDA’s and other regulatory requirements for collecting and managing clinical data. The focus was on information relevant to industry executives and included discussions how to select vendors for running clinical trials and managing clinical data.

First, Colleen Cox, Senior Manager, Data Management, Infinity Pharmaceuticals, provided an overview of the function of a CDM in a pharmaceutical/biotech company and how CDMs ensure that clinical data is accurate, logical, consistent, and complete. Dan Ringenbach, Sr. Enterprise Architect, AstraZeneca, Research and Development Information, then provided an overview of existing and future technologies that may be used in clinical data management, including “the Cloud”, mobile platforms, as well as ways to manage the increasing trend towards electronic clinical data information. With the goal of “seamless integration”, various technologies may be used to create data dashboards that have the potential to deliver increased data quality and reliability. With the increased information, organizations such as the Clinical Data Interchange Standards Consortium (“CDISC”) have emerged to help develop standards for the acquisition, submission, and exchange of clinical research data, as was explained by Shannon Labout, CDISC Expert and Authorized Instructor. FDA wants data that conforms to CDISC standards, Labout said, which may be required in the near future.

Jason Raines, Head, Global Data Operations, Alcon Laboratories, Inc., provided a comprehensive look at how to select, negotiate, and contract electronic data capture (“EDC”) vendors that are frequently utilized in clinical trials. Once an EDC provider is selected, it is important to develop an effective implementation and roll-out plan to provide a structured approach for success. Raines suggested testing an EDC vendor with a pilot before committing resources to one vendor and to develop metrics to demonstrate value from the vendor’s program going forward. Hand-in-hand with selecting an EDC, Anne C. Hansen, Senior Study Data Manager, Genetech, Inc. and Roche Ltd., explained how the EDC vendors can work with contract research organizations (“CROs”).
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research.jpgOn August 27, 2013, FDA issued a new guidance, “IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed“. An IRB is an appropriately-constituted group that has been formally designated to review and monitor biomedical research involving human subjects. Following FDA’s regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. Accordingly, IRBs serve an important role in the protection of the rights and welfare of human research subjects.

The Guidance applies to drugs, biologics, and medical devices and was developed in consultation with the Department of Health and Human Services Office for Human Research Protections (“OHRP”), largely based on recommendations from previously-issued resources. FDA said that it issued the guidance to clarify the Institutional Review Board (“IRB’s”) responsibilities related to the selection of clinical investigators and research sites, because these items are normally considered a sponsor’s responsibility yet they have an impact on the rights and welfare of study subjects. The recommendations in the guidance apply to any IRB, whether serving as a local or centralized review process for multi-site studies. This guidance was developed as part of FDA’s and OHRP’s efforts to harmonize the agencies’ requirements and guidance for human subject protection.

While sponsors of clinical research select clinical investigators who are “qualified by training and experience as appropriate experts,” IRBs have a role in reviewing the investigators’ qualifications to conduct clinical research as proposed in a study protocol. Depending on the IRB’s relationship to the institution conducting the investigation and knowledge of the research, the IRB may already know that a proposed investigator is qualified to conduct the research or may need to dig deeper. In particular, for more high risk investigations, FDA and OHRP expects IRBs to apply a greater amount of scrutiny, especially if the study involves a sponsor-investigator, is outside the investigator’s expertise, or involves other characteristics that may increase risk to human subjects. For example, an IRB may observer, or have a third party observe, the consent process and the research.
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spongescrub.pngOn June 4, FDA announced in the Federal Register that they were considering release of de-identified data sets in an effort to provide greater access to clinical and preclinical study data for researchers. This collaboration with the National Institutes of Health (“NIH”) would presumably work like other public databases NIH has supported over the years to provide access to medical data for research purposes. As a researcher, I (Eric) used NIH databases like the Lung Image Database Consortium (“LIDC”) and Reference Image Database to Evaluate Response (“RIDER”) sets of Lung computer tomography (“CT”) scans to gather anatomic information about the potential patient population to make product design choices. FDA’s proposal offers both potential benefits and harms to consider.

FDA recognizes that clinical study data sets are underutilized for the scientific understanding that they can provide. As a rule, preclinical and clinical studies are very expensive propositions that produce high quality data but receive limited publication, granting few in the research community with access to the raw data. This is understandable, in part, because sponsors wish to both protect their clinical data from competitors who may copy or undermine it, as well for protection of their intellectual property. This limited access prevents that data from being included in certain meta analyses studies. Meta analysis provides the numbers needed to identify lower frequency events and weaker correlations in the data. If a correlation does not reach the widely recognized p-value of 0.05 or lower, the scientific community is hard pressed to consider it a proven hypothesis. Meta analysis combines several studies and can produce “significant” results based on the increased size of the dataset. FDA has access to the raw data from clinical studies submitted with new product applications as well as other databases, however, it does not have the resources or mandate to perform this type of research.

FDA notes that there are potential hazards to this disclosure. FDA’s call for comments states that FDA is not a covered entity for the purposes of the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”). However, patients who have signed up for clinical trials generally have agreed to have their information used for certain purposes, often including publication. For the most part, patients understand that such data may be reported in the aggregate.
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On May 2, Algorithme Pharma, an early-stage clinical contract research organization (“CRO”) based in Laval, Canada, hosted a Science Symposium, “Innovative Solutions to Common Clinical & Bioanalytical Challenges“. First, Catherine Konidas, Vice President, Global Business Development, Algorithme Pharma, , presented a comparison of clinical trials in the U.S. versus Canada. The group explained the benefits of conducting Phase I clinical trials (early stage studies in healthy human subjects to determine a proposed therapy’s safety) in Canada. For each Phase I research to be conduced in Canada, Health Canada, the FDA equivalent regulatory agency, requires Health Canada forms including a clinical trial agreement (“CTA”), an investigator brochure, a protocol, informed consent, CTD summaries, and an overall quality summary. Unlike FDA, Health Canada does not require quality, non-clinical, and clinical reports (only summaries are required) as well as new related publications. In the opinion of Algorithme Pharma, these differences may save time. On the other hand, unlike FDA, Health Canada requires one CTA per clinical trial versus an open investigational new drug exemption for FDA that permits protocol amendments. Similar to FDA, there is a 30-day default for Health Canada to review a CTA, but in Algorithme Pharma’s experience, it usually takes 21 days before Health Canada reviews and permits each study to begin. Also, while an ethics committee review is required for approval, it can be conducted in parallel, which may also save time. In Algorithme Pharma’s experience, it usually takes 58 days via FDA’s procedures before a Phase I study may begin versus 33 days via Health Canada’s procedures, which may be of value for sponsors.

EMA Logo.jpgThe European Medicines Agency (“EMA”) has released their report giving detailed information regarding numbers of patients, sites and inspections with respect to pivotal clinical trials submitted in marketing authorization applications (“MAA”) between January 2005 and December 2011.

As we noted in a previous blog there has been an increase in concern amongst regulators and the public about how well clinical trials are conducted from an ethical and scientific/organizational standpoint, and especially with regard to good clinical practice (“GCP”) compliance. An applicant has to provide information in every MAA regarding the location, conduct and ethical standards applied in respect of the clinical trials conducted in third countries.

The report relates mainly to new applications (485), line extensions (95), and variations where new clinical trial information was provided (97). Generic applications are included as part of the new applications, but they generally do not add much to the number of patients, because these applications are mainly based on small bioequivalence trials, but they do provide information on the locations where these trials were conducted.
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For some time now, there have been strident calls for the publishing of all clinical trial data. The pressure has arisen due to revelations that companies may have hidden crucial clinical data that might have shown that the drug being tested was not as efficacious or even as safe as they appeared from quoted trial results (see, for instance, a previous blog here). The campaign group AllTrials has brought together several people and groups (including for example David Tovey, editor The Cochrane Library; Ben Goldacre (book Bad Pharma); Carl Heneghan, Centre for Evidence-Based Medicine, University of Oxford) because, as they put it:

Around half of all clinical trials have not been published; some trials have not even been registered. If action is not taken urgently, information on what was done and what was found in trials could be lost forever, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated unnecessarily.

Key publications like the British Medical Journal and research bodies such as the Medical Research Council and the Wellcome Trust agree, the trust encouraging its grant recipients to release their trial data.

The European Medicines Agency (“EMA”) has been looking at this for some time, with the same aim in mind and is trying to develop a workable policy to enable the data to be published. Indeed it is thought that in the next few weeks, major players in the United Kingdom’s medical community will meet to try and take things further in a more practical manner.
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alheimers.jpgOn February 5, 2013, FDA announced the availability of Draft Guidance relating to the development of drugs for the treatment of early stage Alzheimer’s disease. The Draft Guidance, titled, “Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease” addresses: (1) diagnostic criteria for early stage Alzheimer’s disease; (2) appropriate clinical outcome measures; and (3) ways to demonstrate disease modification. Addressing these issues in early stage Alzheimer’s disease poses unique difficulties, because patients may have little to no impairment of global functioning. FDA is seeking public comment on the Draft Guidance within sixty days.

The Draft Guidance provides FDA’s current thinking on useful diagnostic criteria for early Alzheimer’s disease. FDA cited useful research in developing diagnostic criteria, such as the research criteria for prodromal Alzheimer’s disease and preclinical Alzheimer’s disease. Specifically, FDA also cited as useful efforts by the research community to incorporate biomarkers into the diagnostic criteria. FDA concluded that, “we support the concept of enriching trial populations with patients most likely to progress to more overt dementia, using both clinical biomarker-based criteria.” FDA also indicated, however, that FDA could not formally endorse any specific diagnostic framework, because more work was necessary to assess the specificity and sensitivity of these criteria, as well as the validation of these methodologies.

The Draft Guidance also provides FDA’s current thinking on ways to establish clinical efficacy in trials involving patients suffering from early stage Alzheimer’s disease. While FDA requires a co-primary outcome measure to demonstrate efficacy on both cognitive and functional levels for clinical trials on the dementia stage of Alzheimer’s disease, in the draft guidance, FDA acknowledged that these endpoints may be impractical for patients suffering from early stage disease. Therefore, FDA indicated that for early stage disease “clear evidence of an effect on delaying cognitive impairment may provide sufficient evidence of effectiveness.”
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Thumbnail image for Thumbnail image for supremecourt.pngEarlier this week, the U.S. Supreme Court denied GlaxoSmithKline’s certiorari petition in a case that would have helped clarify the scope of 35 U.S.C. § 271(e)’s safe-harbor provision. The issue facing the Court was whether section 271(e)(1) applies to postmarketing activity as well as premarketing activity.

Section 271(e), which states that it is not an act of infringement to make, use, offer to sell, or sell a patented invention “solely for uses reasonably related to the development and submission of information under [federal drug laws],” does not include a time limitation. The question about timing was highlighted in two recent Federal Circuit cases. In Classen Immunotherapies, Inc. v. Biogen Idec, 659 F.3d 1057 (Fed. Cir. 2011), the Federal Circuit explained that “§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration.” Last year, however, a different panel of judges in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., 686 F.3d 1348 (Fed. Cir. 2012) held that post-approval studies performed for the FDA fall within § 271(e)(1)’s safe harbor and explained that Classen held that 271(e)(1) “does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained.”

As previously blogged on here, the Solicitor General had urged the Supreme Court to deny GSK’s petition in the Classen case. Despite a belief that the Federal Circuit erred in Classen, United States Solicitor General Donald Verrilli offered the following reasons why the Supreme Court should deny certiorari: (1) the Federal Circuit’s Momenta decision sufficiently clarified and narrowed the Classen holding; (2) it was unclear whether the safe harbor applied to the types of patents at issue in the Classen case; and (3) the petitioners were not entitled to the safe harbor protection regardless of the Supreme Court’s interpretation of the provision.
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