Food and Drug Administration

Congress is currently considering two bills that would dramatically alter the ways in which all federal agencies develop and publish rules. If enacted, both would create significant new obligations for agencies such as CMS and the FDA, expand the scope of judicial review of rules, and would increase the potential for political influence over the rulemaking process. Both bills passed the House on party-line votes, and are under consideration by the Senate.

The first bill, H.R. 5, would overhaul multiple phases of the federal rulemaking process. These proposed changes would make the rulemaking process significantly longer and more complex for agencies, and includes provisions that could prevent some rules from ever taking effect. The key provisions of the bill are summarized below:

  • Prior to publishing any rule (1) with an expected annual impact of $100 million or more, (2) that may reduce employment, or (3) that involves a novel legal or policy issue, an agency would have to publish an advance notice that it intends to publish a proposed notice of rulemaking, and must solicit comments on the notice. A proposed rule could only be published after this new additional process is complete.
  • Whenever an agency publishes a proposed rule for public comment in any of the categories described above, it would have to explain the basis for the rule, the data it relied on, and would have to explain the alternatives to the rule and justify why they were not adopted. In addition to the current public comment period, once a proposed rule was published an interested party could then request a hearing to contest the quality of the information relied on by the agency. Any resolution of this new step would slow down the rulemaking process further.
  • In all cases where a rule is expected to have an annual impact of at least $1 billion annually, the agency would now be required to conduct a public hearing limited to fact issues. This would add to the time and cost of publishing a new or revised rule.
  • When a final rule is published, the agency would be required to explain in the preamble to that rule why the rule will have the lowest possible cost unless it involves public health, safety, or welfare.
  • All agencies would be required to publish all documents considered by an agency prior to publishing the rule.  This would eliminate the deliberative process privilege that has been in place for decades, which is intended to promote the exchange of views within an agency, and may have a chilling effect on agency deliberation. In many cases, a final rule could not take effect until all of the information relied on by the agency had been made available electronically for at least six months unless the agency or the President claims an exception.
  • Recipients of federal funds would be prohibited from advocating for or against the rule, or appealing to the public to either support or oppose the rule.
  • Guidance documents issued by agencies, including manuals, circulars, and other subregulatory publications would no longer have any legal effect and could not be relied on by the agency for any actions. The bill does not explain how many important parts of federal programs, such as the administration of grants or cost accounting for hospitals in the Medicare program would be handled. These and other programs rely heavily on the detailed information found only in agency manuals and guidance. Without these guidelines, health care providers, suppliers, manufacturers, and researchers among others would find it increasingly difficult to comply with federal laws.

The bill would also make drastic changes in the scope of any judicial review of published agency rules. The bill would overturn the Supreme Court’s landmark Chevron decision, which established the principle that when an agency is charged with administering a statute and interprets ambiguous statutory language in a regulation, courts will defer to the agency’s permissible interpretation of the law. In its place, the bill would authorize courts to review all questions of law involving a regulation without giving weight to the agency’s experience or expertise. Courts would be empowered to impose their own constructions of the law on an agency, upending decades of precedents. This has the potential to increase federal courts’ dockets and place those courts in the position of reviewing technical information without all of the resources available to conduct a review. In addition, by allowing courts to decide cases without relying on the agency’s rationale, this increases the potential for inconsistent decisions and confusion among regulated entities such as health care providers, suppliers, and manufacturers seeking to comply with federal laws.

The second bill, H.R. 26, focuses more on expanding Congress’s control over the rulemaking process once an agency has completed the public notice and comment procedure under current law. It also expands the legislative veto over rules, which currently is authorized only when Congress disapproves of a rule and requires the President’s concurrence.

Under the bill, agencies would be required to report all new rules to Congress, and must identify all “major rules” as determined by the Office of Management and Budget that (1) will have an annual impact of $100M or more, (2) increases costs or prices, or (3) will have a significant impact on competition, employment, investment, or foreign trade. The report to Congress must also contain an analysis of the projected number or jobs that would be gained or lost as result of the rule. All major rules with the exception of those necessary for an emergency, enforcement of criminal laws, or to implement a trade agreement would not go into effect unless both houses of Congress approve the rule by a joint resolution within 70 legislative days after the agency submits its report. There is only one chance to obtain approval of a major rule during a session of Congress; if the joint resolution is not approved, or if no action is taken, the bill would bar Congress from considering a second resolution on the same rule during the same two-year session of Congress. This would allow Congress to override an agency and force the agency to begin the rulemaking anew, if at all. Congress would retain the authority to disapprove all other rules by a joint resolution. The bill also allows for judicial review of Congress’s actions only to review whether or not it followed the procedure in the statute; the merits of any action would be unreviewable.

In addition to expanding control over prospective rules, the bill would also add a sunset provision for existing rules. All agencies would be required to review current rules at least once every ten years and report to Congress; if Congress then failed to enact a joint resolution to retain the rules, they would be nullified.

Although the bills passed the House, it will be much harder for the Senate to pass them as well. Under Senate rules, 60 votes are required to end debate and bring the bills to a vote. Since the Republicans only hold 52 seats, they would need additional votes from Democrats in order for the bills to pass.

Early January has seen the release by FDA of a flurry of information on drug and device manufacturer communications, largely reaffirming FDA’s long-held approach to restricting manufacturer communications regarding off-label uses of approved drugs and medical devices. The most significant positive development arising from these documents is the Agency’s concession on proactive pre-approval communications with payors about investigational drugs and devices, allowing certain information to be provided to payors prior to a product’s approval. FDA’s guidance documents issued this week also clarify some grey areas surrounding the circumstances under which manufacturers may communicate about information that is consistent with or related to an approved indication, but is not included in approved product labeling.

While these pronouncements provide drug and device manufacturers with some additional leeway in their communications regarding investigational products and certain information about the approved uses of their products that is not included in the approved labeling, they do not address long-standing questions regarding the circumstances under which manufacturers may communicate about unapproved uses of their products in light of recent First Amendment case law. Instead, these last words of the Agency under the outgoing administration signal that, at least under the direction of current administration, FDA is not inclined to significantly expand manufacturers’ ability to communicate regarding unapproved uses of their products without the risk of enforcement. The eventual impact of the new administration on FDA’s approach to off-label communications remains a significant unknown.

In draft guidance on Drug and Device Manufacturer Communications with Payors, Formulary Committees and Similar Entities – Questions and Answers released on January 18, FDA signifies its acceptance of the position long held by industry and payors alike that payors need access to information regarding investigational drugs and devices to help them plan and budget for coverage of these products once they are approved. In the draft guidance, FDA states that it will not object to manufacturers providing payors with “unbiased, factual, accurate and non-misleading” information regarding investigational drugs and medical devices, provided that those communications include a clear statement of the investigational status of the product and that its safety and effectiveness have not been established, along with information regarding the stage of product development of the product.

Information that may be provided by manufacturers in accordance with FDA’s recommendations in the draft guidance includes information about the product such as its drug class or design, the indication sought and the patient population under investigation, a factual presentation of the results of clinical and pre-clinical studies without any conclusions regarding the product’s safety and effectiveness, the anticipated timeline for FDA approval, product pricing information, and anticipated marketing strategies and product-related programs and services, such as patient assistance programs. FDA also recommends that manufacturers update payors with any significant new information about the investigational product that differs from information previously communicated to them.

As suggested by its title, the primary focus of the draft guidance is on the communication of health care economic information (“HCEI”) regarding prescription drugs to payors, interpreting the changes to FDAMA Section 114 included in the 21st Century Cures Act that was signed into law in December. Notably, unlike FDA’s recommendations regarding pre-approval product communications with payors, this portion of the draft guidance does not apply to HCEI regarding medical devices. The draft guidance also makes it clear that the expanded HCEI communications permitted by FDAMA 114, as amended, are limited to payors, and similar flexibility in the levels of evidence required to support HCEI communications to payors do not apply to communications with health care providers or consumers. Additionally, consistent with the statute, the draft guidance limits the HCEI that may be provided to information that “relates to” an approved indication, confirming that FDA does not currently intend to permit the proactive dissemination to payors of HCEI related to off-label use.

In a series of questions and answers, FDA provides recommendations regarding the types of HCEI that may be provided, the scope of the payor audience to which this information may be provided, the types of competent and reliable scientific evidence that may be relied upon, the information that must be disclosed along with HCEI provided to payors, and perhaps mostly usefully, examples of the circumstances under which FDA will determine HCEI to relate, and not to relate, to an approved indication. FDA describes the categories of information that will be deemed to relate to an approved indication, even if they do not appear within, or vary in some respects from, the approved labeling; provided that the information is not inconsistent with the approved labeling. These include, among others, information on duration of treatment, burden of illness, length of hospital stay, information including actual patient use of an approved drug that varies from the approved dosing regimen, and information derived from clinical data demonstrating an effect on a validated surrogate endpoint or a comparison of safety and effectiveness with another drug or intervention.

FDA’s approach to “related” information in the draft guidance is similar to that taken in another draft guidance it released on January 17 on Medical Product Communications that are Consistent with the FDA-Required Labeling – Questions and Answers. In the Medical Product Communications draft guidance, FDA provides recommendations for manufacturers of drugs and medical devices on communications, including communications with health care providers, consumers and payors and in promotional materials, regarding information that is not included within the FDA-approved package labeling, but is consistent with that labeling.

In determining whether information provided by manufacturers is consistent with the product’s approved labeling, FDA will consider three factors. First, FDA will compare the information to the conditions of use in the approved labeling. To comply with the recommendations in the guidance, the information must relate to an indication, patient population, and dosing and administration instructions within the scope of those set forth in approved label, and it must not be inconsistent with any use limitation or directions for handling or using the product in the approved labeling. Second, the suggestions regarding the use of the product in the HCEI information must not increase the potential for patient harm relative to information in the approved labeling or otherwise adversely impact the risk-benefit profile of the product. Finally, the directions for use in the approved labeling must allow the product to be used safely and effectively under the conditions of use suggested in the HCEI information distributed by the manufacturer. If all three of these factors are met, FDA will not view that information, alone, as evidence that the manufacturer intends to promote the drug or device for a new intended use.

To assist manufacturers in applying these factors, the guidance includes examples of the types of communications that are, and are not, consistent with a product’s approved labeling. In describing the types of evidence required to support the disclosure of information that is not included in, but is consistent with, the approved labeling, FDA states that the data must be scientifically and statistically sound to support the representations made by the manufacturer to avoid being false or misleading, but because the safety and effectiveness of the product for the approved indication has already been established, the evidence need not meet the applicable approval or clearance standard for the product. For drug products, this means that two adequate and well-controlled clinical trials will not be required. The evidence must, however, be accurately characterized and any material limitations on the evidence must be clearly and prominently disclosed in language appropriate for the intended audience.

FDA also has, within a ten day period, released two other pieces of information relating to drug and device manufacturers’ communications regarding their products. On January 9, FDA issued a Final Rule on Clarification of When Products Made or Derived From Tobacco Are Regulated as Drugs, Devices, or Combination Products; Amendments to Regulations Regarding “Intended Uses”, clarifying the Agency’s position that a determination of a regulated product’s intended use may be determined based upon the totality of the evidence of the manufacturer’s objective intended use of the product, including the manufacturer’s knowledge of the product’s actual use for an off-label indication in practice.[1]  FDA states in the preamble to the Final Rule, however, that it will not bring an enforcement action based solely on a manufacturer’s knowledge that an approved or cleared product is being prescribed or used for an unapproved use.

The Proposed Rule released in September 2015 deleted from the drug and device intended use regulations at 21 CFR §§ 201.128 and 801.4 a reference to a manufacturer’s knowledge of off-label uses, specifically the statement that “[Intended use] may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised.” Many commenters on the Proposed Rule had interpreted that deletion as excluding a manufacturer’s knowledge of off-label use from the evidence that may be relied upon to establish a manufacturer’s intent to promote a drug or device for an off-label use. The preamble to the Final Rule expresses FDA’s disagreement, and clarifies that FDA proposed deleting that language merely to avoid a potential misinterpretation that a manufacturer’s knowledge of an unapproved use of an approved or cleared medical product, without more, automatically triggers a requirement for that manufacturer to provide additional labeling for the unapproved use. FDA asserts that its intent was not to change the scope of information that could be relied upon as evidence of a manufacturer’s intended use of the product.  The amended language set forth in the Final Rule provides that “”intended use may be shown, for example, by circumstances in which the article is, with the knowledge of such person or their representatives, offered and used for a purpose for which it is neither labeled nor advertised.”

In the preamble to the Final Rule, in response to comments that existing First Amendment jurisprudence restricts FDA from bringing enforcement actions based on truthful and non-misleading speech regarding a product’s off-label use, FDA states that it is separately examining its rules and policies relating to firm communications regarding unapproved uses of approved and cleared medical products, and while those broader policy considerations are being addressed separately from the Final Rule, “[n]evertheless, it is important to note here that we do not agree with the assertion that the current case law allows FDA to consider speech as evidence of intended use only when it is false or misleading.” FDA cites recent Second Circuit precedent[2] to support its view that the Second Circuit’s 2014 Caronia decision does not foreclose the government’s ability to prove misbranding using promotional speech as evidence that a drug is intended for an off-label use. FDA goes on to describe the significant public health considerations that the Agency believes support its approach to limiting manufacturer communications regarding off-label uses of their approved or cleared products.

FDA makes similar assertions in a document posted to the docket for the November public hearing on Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products entitled, “Memorandum: Public Health Interests and First Amendment Considerations Regarding Unapproved Uses of Approved or Cleared Medical Products.” In a notice published in the Federal Register on January 19, 2017, FDA announces that it has reopened the comment period that was opened in connection with the public hearing on off-label communications that took place November 9 and 10, 2016 to allow interested parties an opportunity for additional comment based on the content of the memorandum and the two draft guidances discussed above. In this memorandum, FDA describes in detail the public policy considerations guiding its assessment of its restrictions on off-label communications, and the legal authority it believes supports its restriction of these communications and their use as evidence of intended use to support misbranding actions. FDA also describes its views on several alternative approaches to addressing the public health interests at issue.  FDA seeks additional comments on its views expressed in the memorandum and potential alternative approaches to regulating manufacturer communications regarding off-label indications of their approved products.  The docket will remain open until April 19, 2017.

[1] In addition to its provisions specific to determinations of when a tobacco product will be regulated as a drug or device, the Final Rule also amended intended use regulations at 21 CFR §§ 201.128 and 801.4.

[2] United States ex rel. Polansky v. Pfizer, Inc., 822 F.3d 613 n.2 (2d Cir.2016).

Where does the line fall between good faith and criminal intent? That was the question that a Massachusetts federal jury faced in July as it deliberated criminal charges against William Facteau and Patrick Fabian, ex-Acclarent executives, who were indicted on multiple charges of fraud and misbranding a medical device. Acclarent’s device, the Relieva Stratus Microflow Spacer (“Stratus”), was cleared by the FDA for use as a spacer to maintain an opening in the sinus. Although the FDA expressly rejected Acclarant’s request to expand the indicated use of the device to include delivery of drugs, the government alleged that Acclarent promoted Stratus as a delivery method for the steroid drug Kenalog.

The arguments at trial focused on whether, in the defense’s view, Acclarent had done no more than claim that it had a good faith belief that it could promote the proven success of Stratus for delivering Kenalog, or the government’s position that the company’s leadership deliberately evaded the FDA’s requirements in order to put a product on the market without adequate data. The defense highlighted how, after receiving clearance for Stratus as a spacer, Acclarent asked the FDA to expand the indications for use to include the delivery of Kenalog, a corticosteroid. The FDA would not approve the expanded indication without multiple clinical trial data. The government, on the other hand, emphasized that Acclarent withheld this information when promoting Stratus to Ethicon, a subsidiary of Johnson & Johnson that bought Acclarent in 2010. After the deal closed and Ethicon realized Stratus lacked FDA clearance to deliver steroids, Ethicon ordered Acclarent to stop all off-label promotions to doctors and to notify the FDA. While Acclarent did contact the FDA, evidence shows that Facteau and Fabian continued encouraging sales representatives to promote Stratus for the delivery of Kenalog. An Acclarent sales representative testified that sales training focused on how to promote the use of Stratus with Kenalog without directly promoting the off-label use, and the videos used to train physicians showed Stratus being used to deliver a white substance resembling the steroid.

Ultimately, after six weeks of trial and almost three days of deliberations, the jury decided that good faith won over the alleged criminal intent. Fabian and Facteau were acquitted of all felony charges but convicted of ten misdemeanor counts of misbranding and adulteration of Stratus. The jury concluded that while the off-label promotion rules were broken, there was not enough evidence to conclude that the defendants had the intent to mislead or defraud doctors or the FDA. The misdemeanor convictions were based on statutes that impose strict liability, for which no finding of a criminal intent is required. A misdemeanor violation of the Food, Drug and Cosmetics Act (“FDCA”) has a maximum sentence of a year in prison per count, a year of supervised release, and a fine of either $100,000 or double the gross gain or loss.

When the dust settled from the jury’s verdict, Facteau and Fabian submitted a formal request for acquittal of the misdemeanor convictions. If the federal judge denies their request for judgment, the ex-Acclarent executives will seek a new trial. The outcome of this case may affect how medical device manufacturers deal with FDA oversight, particularly where a manufacturer seeks to market a device for a specific use but only has data addressing a more basic purpose. At the same time, the outcome may serve as an indication to the FDA that bringing similar criminal charges for off-label promotion in the future may prove more difficult than anticipated.

This post was written with assistance from Megan E. Robertson, a 2016 Summer Associate at Epstein Becker Green.

Despite popular opinion, lawyers and judges are human and sometimes the facts of a case make it near impossible for judges to play the role of the modest umpire calling balls and strikes described by Chief Justice Roberts in his confirmation hearing.  Sometimes, bad facts make bad law because the plaintiff is so sympathetic that the just ruling may not be the “right” one.  Fachon v. U.S. Food and Drug Administration et al., appears to be the epitome of this.

Earlier this year, a 20-year old man, Eugene Neil Fachon, was diagnosed with Diffuse Intrinsic Pontine Glioma (“DIPG”) a form of brain cancer for which there is no cure.  His doctors told him he had only three months to live.  At the time of his diagnosis, Mr. Fachon was pursing an engineering degree at Northeastern University in Boston.  While his fellow college students were trying to figure out where to go for spring break, Mr. Fachon was trying to figure out what to do next in light of his grave prognosis.  Instead of undergoing the standard treatment, radiation, which may have had the potential to extend his life for up to three additional months, he decided to participate in a clinical trial that was intended to investigate the efficacy of Antineoplaston therapy.  The clinical trial was being performed pursuant to an Investigation New Drug Application (“IND”) that was in effect, pursuant to 21 CFR 312.40, at the time Mr. Fachon was enrolled.[1]  Mr. Fachon enrolled in the study on March 13, 2016, becoming the first and only subject enrolled.  On or about the same day Mr. Fachon began receiving the investigational drugs, April 21, 2016, FDA placed a clinical hold on the clinical trial and ordered the study site to stop administering the investigational drugs to Mr. Fachon.

After being unable to convince FDA to allow him to continue receiving the investigational drugs, despite the clinical hold, Mr. Fachon filed suit seeking a preliminary injunction, a permanent injunction and temporary restraining order prohibiting FDA from enforcing its clinical hold and requiring FDA to allow him to continue receiving the investigational drugs.  Mr. Fachon argued that FDA violated his due process rights under the 5th and 14th Amendments because FDA failed to notify Mr. Fachon of its intent to impose a clinical hold and grant Mr. Fachon an opportunity to be heard.  On May 17th, Judge John J. McConnell, granted Mr. Fachon the temporary restraining order he requested.

In granting the temporary restraining order, Judge McConnell concluded that once Mr. Fachon started participating in the clinical trial, he had a protectable interest in continuing his participation that entitled him to due process.  The key aspects of due process are notice and an opportunity to be heard.  Thus, Judge McConnell concluded that before FDA could take away Mr. Fachon’s right to continue receiving the investigational drugs, FDA may have been required to notify Mr. Fachon and provide him an opportunity to convince FDA otherwise.

However, other than concluding that this right arose once Mr. Fachon started receiving the study drug, Judge McConnell did not provide much of explanation about this right, including the source of this right or the scope of the right.

I am not saying that Judge McConnell was wrong in granting the temporary restraining order, to the contrary.  I agree that the balance of the equities favored granting the temporary restraining order, but Judge McConnell could have (and I think should have) granted the temporary restraining order without reaching the conclusion on the merits of the case and without concluding that Mr. Fachon was entitled to due process.

Because Judge McConnell chose to recognize this right, this case has the potential to significantly impact how clinical trials are conducted.  To the extent participants in clinical trials are entitled to due process, some questions will need to be answered, including:

  • Would subjects who benefit from the investigational product during the study be entitled to continue receiving the investigational product until it is approved by FDA? This is not an unusual concept as other countries grant subjects this right already.
  • How does this impact an investigator’s ability to remove a subject from a study without the subject’s consent? An informed consent is required to describe the “[a]nticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent.”[2] However, an informed consent cannot include any language through which a subject waives any of his or her legal rights.
  • Before FDA places a clinical hold on a study that includes a requirement that enrolled subjects stop receiving the study drugs, will FDA be required to notify all study subjects and provide them an opportunity to be heard before the clinical hold goes into effect?

These are complicated issues that are best suited for legislative and regulatory solutions.  Therefore, hopefully the parties and the judge can find an appropriate resolution to this case that allows Mr. Fachon to pursue this experimental treatment without opening up Pandora’s box.



[1] Although the Plaintiff’s motion characterizes the clinical trial as “FDA-Approved”, FDA does not necessarily “approve” clinical trials.  Rather, FDA regulated clinical trials must be performed pursuant to an IND that is “in effect” and an IND is deemed to be effective the earlier of 30 days after FDA receives the IND or FDA notifies the clinical Sponsor that the clinical trial may begin. 

[2] 21 CFR § 50.25(b)(2)

On May 17, 2016, FDA issued Draft Guidance for Industry on Use of Electronic Health Record Data in Clinical Investigations (“Draft Guidance”).  This Draft Guidance builds on prior FDA guidance on Computerized Systems Used in Clinical Investigations and Electronic Source Data in Clinical Investigations, and provides information on FDA’s expectations for the use of Electronic Health Record (“EHR”) data to clinical investigators, research institutions and sponsors of clinical research on drugs, biologics, medical devices and combination products conducted under an Investigational New Drug Application or Investigational Device Exemption.

While the recommendations set forth in the Draft Guidance do not represent a significant departure from existing guidance, research sponsors, institutions and investigators should consider the extent to which their existing policies and procedures, template agreements, protocols and informed consent documents should be updated to incorporate FDA’s recommendations.

Specifically, the draft guidance provides additional detail on FDA’s expectations for the due diligence to be performed by sponsors prior to determining the adequacy of any EHR system used by a clinical investigator to capture source data for use in a clinical investigation. FDA expects sponsors to assess whether systems have adequate controls in place to ensure the confidentiality, integrity, and reliability of the data. FDA encourages the use of EHR systems certified through the ONC Health IT Certification Program, and will presume that source data collected in Health IT certified EHR systems is reliable and that the technical and software components of privacy and security protection requirements have been met. Sponsors should consider requesting additional detail in site pre-qualification questionnaires or pre-study visits regarding any EHR system utilized by clinical investigators to record source data, including whether such systems are Health IT certified. Sponsors may also consider the extent to which their existing site qualification policies and clinical trial agreements templates adequately reflect the technical requirements for sites utilizing EHR systems to record source data, the need to ensure that any updates to those systems do not impact the reliability of the security of the data, and the extent to which the data, including all required audit trails, are backed up and retained by the site to ensure necessary access by FDA.

The Draft Guidance also includes recommendations regarding the information it expects to be included in study protocols and informed consent documents. When the use of EHR systems is contemplated, FDA recommends that study protocols include a description or diagram of the electronic data flow between the EHR and the sponsor’s EDC system, along with information regarding the manner in which the data are extracted and imported from the EHR and monitored for consistency and completeness. FDA also recommends incorporation into informed consent forms of information regarding the extent of access to EHRs granted to sponsors, contract research organizations, and study monitors, as well as a description of any reasonably foreseeable risks with the use of EHRs, such as those involving an increased risk of data breaches. While information related to third party access to health information is typically addressed in informed consent documents, specific details related to access to EHRs and their associated risks are less common. Sponsors and research institutions should consider the extent to which their template informed consent documents should be updated to incorporate the best practice recommendation in the Draft Guidance.

In addition, in the Draft Guidance, FDA encourages the development and use of interoperable EDC and EHR systems to permit electronic transfer of EHR data into the eCRFs being utilized for a clinical trial, including the adoption of data standards and standardization requirements of the ONC Health Information Technology (Health IT) Certification Program. While interoperability of EHR and EDC systems offers the promise of increasing efficiency of clinical trial data collection and reducing the transcription errors that commonly result from the maintenance of this information in separate repositories, FDA acknowledges challenges related to the diverse ownership of the data and EHR systems used to capture them, and the confidentiality of clinical trial information, that will need to be overcome in order to realize the benefits offered by interoperability.

On December 23, 2015, the Food and Drug Administration’s (FDA) released draft guidance on the Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base. This was a positive step towards helping pharmaceutical companies invest and implement emerging technologies that improve overall drug quality.

Pharmaceutical companies have spent millions of dollars issuing recalls for products because of a variety of quality issues caused by outdated manufacturing technologies. These issues have caused significant delays in providing patients access to drugs and have the potential of harming patients. Manufacturers have argued that new and emerging technologies will help avoid these kinds of issues but use of such technologies may delay the approval of new drugs. This guidance provides a pathway for pharmaceutical companies wanting to modernize manufacturing technology to help prevent adverse drug quality.

By the very nature of new, innovative technology, the FDA lacks experience reviewing such technologies, which in turn discourages pharmaceutical companies from pursuing such ventures. Given the time it may take for FDA to get comfortable with the technologies, such innovations may add significant time to drug application reviews. To address this, FDA has initiated a new Emerging Technology Team (ETT), through the Center for Drug Evaluation and Research (CDER), to which pharmaceutical companies would be able to submit pre-submission questions and proposals and obtain early engagement to work through the manufacturing design, development and required submission content.

To be accepted into this optional program, the sponsor must submit its proposed plans regarding an Investigational New Drug (IND) or an original or supplemental Abbreviated New Drug Application (ANDA), Biologics License Applications (BLA) or New Drug Application (NDA) in a written request for a Type C meeting to three months prior to the planned submission. The planned submission will need to include any aspects of the submission that FDA would have limited experience with and where the technology could modernize the pharmaceutical manufacturing body of knowledge. The guidance provides as an example an update to a manufacturing line where a contemporary aseptic facility uses highly automated use of isolators to decrease the risk of contamination from the processing line. FDA expects to notify companies as to their status in the program within 60 days of the request.

This guidance reminds industry that the FDA is willing to be flexible and work with applicants to continuously improve and develop new and existing manufacturing processes. This type of collaboration between the FDA and industry may lead to reduced drug shortages and patient risk with respect to drug quality. However, this assumes that the ETT does indeed have adequate resources and expertise to help industry assess novel technologies moving forward.

FDA has recently partnered with PatientsLikeMe, an online patient networking forum, to leverage patient-reported information to bolster its drug safety monitoring efforts. PatientsLikeMe, with its 350,000 members representing over 2,500 health conditions, has collected more than 110,000 adverse event reports on 1,000 different drugs. This partnership, which is in the form of a research collaboration agreement, will provide FDA with access to “real-world” data about patients’ drug and disease experiences (the information provided to FDA is anonymous; so it does not appear, at least at this time, that FDA would be able to follow up with patients who post on the forum). More broadly, this partnership is evidence of increasing interest, among both regulators and pharmaceutical manufacturers, in the value of social media as a tool to identify potential adverse drug reactions and safety issues.

Postmarketing surveillance focuses on tracking the safety of drugs once they’ve reached the market. Such surveillance plays a critical role in ensuring drug safety as premarket clinical trials, which are designed to capture safety issues on the front end, have certain inherent limitations. For example, because clinical trials are conducted under controlled and standardized conditions, they are unable to adequately capture data that reflects “real world” use. That’s where postmarketing surveillance comes in. But FDA’s current postmarketing surveillance system has clear shortcomings.

To monitor potential safety concerns surrounding approved drugs, FDA collects drug adverse event reports and compiles them into its FDA Adverse Event Reporting System (FAERS) database. Such reports are submitted to FDA by patients, healthcare professionals (doctors, nurses, pharmacists, etc.) and pharmaceutical manufacturers. However, only pharmaceutical manufacturers are required to submit such reports; reporting for all others is voluntary. Not surprisingly, the largely passive nature of this system results in significant underreporting. Head of global safety at Novartis, David Lewis, has noted, “Adverse drug reactions (ADRs) are grossly under reported by everyone, including healthcare professionals, but particularly so by patients (emphasis added).” Underreporting by patients is one limitation of FDA’s postmarketing surveillance system that a partnership with PatientsLikeMe may help to address. Yet, another major limitation of the FAERS data arises from uncertainty about whether the reported adverse event was actually caused by the drug (FDA does not require reports to prove a causal relationship and reports often lack sufficient detail for FDA to assess the adverse event). It’s unclear whether access to patient-reported information from forums like PatientsLikeMe will help address this limitation and provide FDA with the robust data it needs to make decisions about drug safety.

Mining data from social media sources, such as PatientsLikeMe, Twitter and Facebook, is undoubtedly picking up traction as a way to help address some of the current limitations in FDA’s postmarketing surveillance efforts. U.S. company, Epidemico, is breaking ground in this space. The company is working to develop algorithms to identify side effects from social media sources. Specifically, it utilizes its “Med-WatcherSocial platform” to find adverse drug reports in social media posts for 1,400 drugs.

Ultimately, obtaining information from social media sources may improve the chances of capturing adverse events that a patient may not complain about to their own physician (or to regulatory agencies).  According to Lewis, “Physicians are great at diagnosing illnesses and noting objective signs, but patients are great at reporting subjective reactions and feelings.” And they often take to social media to do so.

Still, many open questions remain surrounding the use of information posted on social media for postmarket surveillance purposes. How can patient-generated information from social media sources be distilled and used? Can (and should) regulators and pharmaceutical companies reach out to patients posting on social media for follow up? What are the legal and ethical considerations? How will FDA and companies manage the sheer volume of data using the current systems without becoming overwhelmed?  Should “social-media”-specific regulations be developed to account for differences from traditional passive reporting systems?  And, finally, is there a point where collecting more information actually does more harm than good by obscuring true safety signals?  Despite these open questions, interest in this area continues to grow, as regulators, pharmaceutical companies and industry partners work to harness the power of social media to improve drug safety monitoring.

Our colleagues James A. Boiani and John S. Linehan at Epstein Becker Green wrote an advisory on the U.S. Food and Drug Administration’s (“FDA”) introduction of new plans to constrain animal drug compounding with the release of its Draft Guidance for Industry (GFI) #230, Compounding Animal Drugs from Bulk Drug Substances. In this advisory, the parameters of the Draft Guidance are outlined, which suggests that a dramatic shift in the FDA’s enforcement approach may be underway and provides insight into the FDA’s enforcement priorities and its interpretation of the applicable regulatory regime.

Read the full alert online.

While FDA made a push last fall to explore the technical challenges associated with 3-D printed devices (holding a public workshop in October 2014), the Agency’s planned guidance on the topic fell to the “B-list” in FDA’s 2015 medical device guidance agenda. According to the agenda, the Agency will issue a draft guidance document on 3-D printing as “guidance-development resources permit.” In light of the regulatory uncertainty facing 3-D printing stakeholders, this may seem like unwelcome news – but is it?

Recent comments from Agency officials suggest that immediate guidance is unnecessary because 3-D printing, despite prior comments, is “business as usual” regulatory review work for FDA that might not need extensive specialized guidance.  At a conference last month, the director of FDA’s Office of Science and Engineering Laboratories, Steven Pollack, explained that the Agency generally sees 3-D printing as a manufacturing technology, “not something that exotic from what [its] seen before.” Pollack also expressed that the Agency does not feel particularly unprepared to review 3-D printed devices under its current regulatory paradigm.

Still, during a January interview, Pollack did acknowledge that there are some unique challenges that 3-D printing may present for FDA and device manufacturers. For example, he expects that 3-D printed devices may require additional or different testing than is usually done. To minimize regulatory challenges, Pollack recommends that manufacturers looking to market 3-D printed devices participate in pre-submission meetings with FDA review teams. Such meetings can help FDA reviewers get a better understanding of the technology involved in manufacturing the device, which is critical.  However, pre-submissions are, essentially, case-by-case and fact-specific negotiations.  The process, though invaluable, also has some inherent inefficiencies and potential for inconsistencies that Agency-wider guidance can ameliorate.

3-D printing regulatory challenges may also be compounded by difficulties faced by manufacturers earlier in the design and development process.  Dr. Scott Hollister, University of Michigan biomedical engineering professor and developer of a 3-D printed tracheal splint, has identified specific material-related challenges. In an article for PlasticsToday, Hollister cited the following as key issues related to 3-D printing materials: particle size (impacts the laser sintering process), the availability of materials, heat resistance, strength, and degradation rate.

So for now, FDA seems intent to function without specific regulatory guidance.  While this may be a way to bring some advances to market, it seems like there are still regulatory challenges and uncertainties to address, which will likely only multiply as 3-D printed devices are  developed for a greater variety of (and more complicated) uses.  Therefore, the more guidance and transparency FDA can provide to stakeholders, the better. Considering FDA’s 2015 guidance priorities, however, manufacturers hoping for specific regulatory clarity in this space likely will have a while to wait.

One of the most discussed aspects of healthcare has to be how to balance cost, quality and access.  This is especially true when it comes to the pharmaceutical industry, particularly with the rapid growth of and increased focus on highly effective, but highly expensive, specialty drugs.  Discussions about these costs are no longer isolated to negotiations between pharmaceutical companies, PBMs and insurers; instead it appears that price and cost are on FDA’s radar.  stethescope

For example, the Oncologic Drugs Advisory Committee (“ODAC”) hearing, earlier this month, was not only historic because ODAC unanimously recommended FDA approve the first biosimilar product under the Biologics Price Competition and Innovation Act, but it is the first time I am aware of an advisory committee member asking about the cost of the product.  Specifically, Dr. James Liebmann asked whether the biosimilar product would be priced less than the existing reference product.

What is more surprising is that last month a recent survey determined that more than 4 in 10 pharmaceutical executives expressed an openness to FDA taking economic data into account in determining whether to approve a drug product.  Although I think it is important for the country as a whole to consider costs when deciding between treatment options, I don’t think FDA or any government entity should be in a position to prevent a safe and effective product from reaching the market because of its costs.  FDA should only evaluate whether the product is safe and effective and leave it up to the payor to do the cost-benefit analysis.

That being said, a recent study indicates that this analysis may be difficult because a patient’s perception of cost may actually impact how well a drug works.  According to the study discussed in Lenny Bernstein’s article entitled “An ‘expensive’ placebo is more effective than a ‘cheap’ one, study shows,” it appears that the cost of a drug could impact efficacy.  This article discusses a small clinical study in which patients with Parkinson’s disease were told they were going to receive an investigational drug developed to treat their disease.  The patients were told that one of the injections that they would receive contained a version of a drug that cost $100, and that the other contained a version that cost $1,500.  However, in reality, both injections were nothing more than saline.

Leaving aside the ethical issues of deceiving the subjects, the results were pretty amazing.  Specifically, the patients performed better on certain motor skills tests after receiving the injection that they believed contained the more expensive drug than they did after receiving the injection that they believed contained the less expensive drug.  What was more shocking to me was that results associated with the “more expensive” placebo apparently came close to the results associated with the patients’ regular drug, levodopa.

I understand that this study was relatively small and the results may not be generally applicable; however, I think this is something payors and regulators think about as we try to use cost sharing as a way of influencing patient choice and driving down costs.  If we encourage patient’s to choose the less costly alternative, will this negatively impact the efficacy of the treatment?

Additionally, I think this study demonstrates the potential magnitude of the placebo effect.  Therefore, as Congress and other stakeholders think about alternatives to double-blind studies to support approval of new products, in the context of the 21st Century Cures initiative, this should be something they think about.