DID - Oct. 1, 2009 Issue

Vol. 8 No. 191

FDA Provides First Draft Guidance on REMS for Drugs, Biologics

The FDA has issued the first of its long-awaited draft guidances on risk evaluation and mitigation strategies (REMS) for drugs and biologics, sparking concerns from industry that it may add too much time to the approval process.

“The industry’s key questions will include how much this will delay market growth,” Les Funtleyder, an analyst with Miller Tabak, said. If the rules aren’t drafted carefully, they could create “a recordkeeping nightmare,” he added.

The draft, which is the first of at least two on REMS, covers four elements of the process: the format and content of a proposed REMS, assessments and proposed modifications of approved REMS, identifiers to use on REMS documents and how to communicate with the agency about the risk strategies, according to the recommendations to be published in the Oct. 1 Federal Register. A sample REMS proposal is included in the draft, for which comments are due Dec. 30.

“We can't estimate the average time it would take to review REMS,” CDER spokeswoman Crystal Rice told DID. She added that timelines under the Prescription Drug User Fee Act apply to REMS submissions, “although they are only goals, not binding deadlines.” The speed of the review is influenced primarily by the complexity of the REMS, she said.

A REMS submission must include two parts: a proposal with goals and possible elements and a separate supporting document with more information. The submission may also include such elements as a Medication Guide, the draft says. A template is available on the FDA’s website, “Postmarket Drug Safety Information for Patients and Providers,” and may be updated as needed, the draft guidance says.

Elements to assure safe use (ETASUs) may be required if the drug is associated with serious adverse events. ETASUs must include one or more goals to mitigate these risks, and may also have to include monitoring, evaluation, and implementation improvement systems.

The FDA has approved 58 REMS to date — 24 in 2008 and 34 this year. All include timetables for assessment and Medication Guides, 11 include communication plans, and six include ETASUs, all but one of which also includes an implementation system.

The drugs and biologics industries also will want to know how much will it cost companies to administer REMS, and what penalties will they face if they don’t comply, Funtleyder said.

Peter Pitts, president of the Center for Medicine in the Public Interest, told DID earlier this year that although REMS will increase the cost of doing business for pharmaceutical companies, the plans are an appropriate business cost and might offer a path forward for drugs that otherwise would not have been approved because the FDA could not assure their safe use, he said.

“One of the biggest problems is that there is no predictability in the REMS development process,” Pitts said. The agency should provide companies with good guidance, good rulemaking, more predictability and less ambiguity, he added.

The proposed REMS should be organized in the following sections:

  • Product and contact information;
  • Goals, in a statement of overall goals and — when the REMS has one or more ETASUs of a product — one or more goals to mitigate a serious risk;
  • Additional potential REMS elements such as a Medication Guide;
  • Elements to assure safe use and help patients get safe access to drugs with known serious risks;
  • Implementation monitoring system for a REMS that includes ETASUs; and
  • Timetable for submission of assessment of REMS.

Supplemental applications that include a proposed REMS or proposed modifications to an approved REMS should be submitted as prior-approval supplements, not as “changes being effected” supplements, the draft adds. In addition, a proposed REMS submitted after approval and not associated with an existing supplemental application should be submitted as a new supplemental application.

REMS assessments may be required as part of a REMS submission, especially one that is part of an sNDA or sBLA. Applicants may voluntarily submit an assessment of an approved REMS at any time but it requires FDA approval.

The proposals should include a timetable for submitting assessments. The FDA Amendments Act (FDAAA) requires that they be made at 18 months and three years after the REMS is approved, as well as in the seventh year — unless another timetable is specified.

The FDA may unilaterally modify a REMS assessment timetable due to new safety or effectiveness information. If the agency determines that there may be cause for withdrawal or suspension of the drug’s approval, it may set a 15-day timeline for a new REMS assessment.

The draft includes detailed instructions on identifying information that applicants must submit with the REMS document so that it can be tracked, routed and reviewed appropriately.

When communicating with the FDA regarding a proposed REMS, companies should keep in mind that they may include their proposal in the initial submission of an NDA, BLA, sNDA or sBLA, or they may submit it as an amendment to an existing application, the draft says.

When the FDA tells a drug or biologics maker that it must submit a REMS, the company must generally do so within 120 days, the draft says. Companies that had risk minimization action plans (RiskMAPs) before 2007 will generally continue them, although the agency may request that they be redone in REMS format.

Final REMS and appended documents will be referenced in and appended to the approval letter for the application or supplement that contains the proposed REMS, and the documents will be posted on the CDER or CBER websites, according to the draft.

The draft covers voluntary as well as required REMS submissions. Future FDA guidances will address provisions that pertain only to ANDAs and expanded information about REMS assessments and proposed modifications, according to the draft.

“Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications” is available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf. The template for the REMS supporting document is available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm. The list of approved REMS is available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. — Martin Berman-Gorvine


FDA Risk Communication Plan Targets Rules for Promotions

The FDA will evaluate its framework for regulating promotions of prescription drugs to determine if new or revised legislation or regulations are needed, as part of its new Strategic Plan for Risk Communication.

The plan calls for the FDA to strengthen the science it uses to support its risk communications; expand the agency’s capacity to create, disseminate and oversee them; and optimize its policies by developing criteria for when and how to communicate emerging risk information. It says the agency will employ 14 actions in the next 12 months and more than 70 actions over the next few years to improve risk communication.

The plan, released Sept. 30, advocates the FDA use 14 strategies, one of which would ensure patients get useful written information about using prescription drugs, including biologics. Citing its review of a study on consumer medication information, the agency says private sector efforts have not succeeded in meeting congressionally mandated goals that patients get the information on drugs they are taking.

This failure allows the agency to “examine the patient information program anew and potentially take regulatory action to ensure that patients get this information,” the plan says. So the FDA is revisiting its current approach to the content and format of written prescription drug information provided to patients.

The plan calls for the FDA to modernize the regulation of prescription drug promotion. Current rules may create confusion when applied to direct-to-consumer (DTC) advertising, the plan says. For example, regulations require that FDA enforce distinctions in information disclosure between advertisements and labeling although such distinctions are not meaningful to a targeted consumer audience, the plan says.

Other rules do not require the FDA to enforce identical information disclosure requirements within ads and labeling, which results in DTC ads having highly technical content that can be difficult to sort through, the plan adds.

If certain drugs are used by the elderly, for example, the agency should consider their cognitive limitations when considering instructions for use that could make them more likely to be followed, the plan says.

It also advocates that the agency establish a web portal to receive feedback from stakeholders on its risk communications efforts, and issue a guidance on sponsor evaluation of risk evaluation and mitigation strategies for drugs (see related story).

For example, the plan urges the FDA to form more web partnerships similar to the one it has with WebMD. The www.webmd.com/fda site will include information on the safety of FDA-regulated products, including medicines, according to the plan (DID, Dec. 4, 2008).

The plan also calls for the agency to develop templates for agency press releases about regularly occurring events, including approvals, recalls and public health advisories.

The goals the agency hopes to achieve over the next 12 months include:

  • Designing a series of surveys to assess the public’s understanding of, and satisfaction with, FDA communications about medical products;
  • Creating and maintaining a useful, easily accessible internal database of FDA and other relevant risk communication research;
  • Posting pictures of FDA-regulated products affected by Class I or high-priority Class II recalls as part of recall notices/information; and
  • Developing detailed action plans at both agency and center levels for implementing and achieving proposed action steps.

“While PhRMA continues to carefully review the Food and Drug Administration’s Strategic Plan for Risk Communication, we share the agency’s goal of disseminating science-based communication that provides patients and healthcare providers with clear, accurate and understandable information concerning the benefits, risks and appropriate use of medicines,” PhRMA Senior Vice President Ken Johnson told DID.

The FDA recently announced it is seeking industry representatives for the Risk Communication Advisory Committee and has set an Oct. 9 deadline for drug and trade organizations to nominate candidates to serve as temporary nonvoting members on the panel (DID, Sept. 9).

The panel, which was formed in June 2007 to help the agency improve how it communicates product risks and other information to the public, advises the agency on developing plans to communicate product information and on how to effectively reach appropriate audiences with specific product information (DID, June 5, 2007).

The plan is available at www.fdanews.com/ext/files/RiskCommunicationPlan.pdf. — Elizabeth Jones


Discovery Takes Step Nearer Trial Protocol for Surfaxin

Discovery Labs plans to submit a limited clinical trial protocol for Surfaxin by the middle of the fourth quarter after it received additional guidance from the FDA.

A teleconference with the agency addressed the remaining obstacle to approval — concerns about comparability between the supply of Surfaxin (lucinactant) used in clinical trials and the product that would be commercialized, Discovery says in a statement Wednesday. Discovery is seeking approval for a Surfaxin indication to prevent respiratory distress syndrome (RDS) in premature infants.

The company had said it would discuss a limited clinical trial design at the Sept. 29 meeting and whether that trial, while simultaneously employing a biological activity test (BAT), could address the comparability issue (DID, Sept. 14). The FDA suggested the approach in June. The trial design is intended to primarily assess a pharmacodynamic response following Surfaxin administration in preterm infants with RDS, Discovery says.

The FDA indicated in the teleconference that the proposed program to optimize and validate the BAT is reasonable, the company says. The program is intended to confirm that the BAT can adequately distinguish changes in Surfaxin biological activity over time. Discovery says it is confident it will be able to optimize the BAT to the FDA’s satisfaction.

The FDA met with the company in June after sending Discovery an April 17 complete response letter (DID, April 21). The company has had difficulty demonstrating that its BAT and a preterm lamb model of RDS adequately support the comparability and can distinguish changes in Surfaxin biological activity over time. — April Hollis


AAHRPP Adds Conflict-of-Interest Standard

The Association for the Accreditation of Human Research Protection Programs (AAHRPP) has issued the first major revision of its standards, which takes effect Oct. 1, setting a new standard for transnational research and conflicts of interest.

The organization also added or tightened standards on community-based research and data and safety monitoring, reducing the number of standards from 22 to 15 and the number of elements, which are grouped under a standard, from 77 to 60, according to a Wednesday statement. The final standards are slated to be posted on AARHPP’s website by Oct. 1, spokesman David Ward told DID.

AAHRPP says it plans regular comprehensive reviews of the standards as part of its quality improvement initiative. The biggest change is the new standard for transnational research, Ward said. It recommends that an organization operate under the same standards as its own country, or when it operates in a country with higher standards, reach that bar.

The conflict-of-interest standard, previously considered an element, recommends that organizations establish and follow procedures to identify, manage and minimize or eliminate conflicts of interest and apply the same procedures for researchers and research staff, Ward said.

AAHRPP also has built increased interpretative flexibility into the new standards, which have been regrouped into more logical categories, the association says in the statement.

A draft version of the new standards was released June 1, with a public comment period ending July 30. The final standards will be added to the website, but organizations applying for accreditation through Feb. 28, 2010, may follow either the previous or revised standards. After that date, only the revised standards will be valid.

The standards will be available at www.aahrpp.org. — Martin Berman-Gorvine


FDA Proposes Postmarket Reporting Rules for Combo Products

Sponsors of combination products should follow the postmarket reporting requirements of the type of application used to get the FDA’s approval or clearance, as well as provide additional reports for the product’s constituent parts, under a proposed rule issued by the FDA.

The additional reports would be necessary only if the original approval or clearance did not require them or if they were required by rules for the constituent part at times earlier than those mandated by the original approval.

Regardless of the type of application under which a combination product could be approved — NDA, BLA, premarket approval (PMA) or 510(k) — all combination products must report the following, if applicable for their constituent parts:

  • A five-day report related to the device constituent part after an event that necessitates remedial action to prevent an unreasonable risk of substantial harm to public health. Reporters also must maintain a record of the report;
  • A 30-day report if the device would likely cause or contribute to death or serious injury if the malfunction were to recur. These reports apply to Class II and III devices that are permanently implantable, life supporting or life sustaining. Reporters also must maintain a record of the report;
  • A 15-day alert report for a drug or biological product constituent part after an adverse experience that is both serious and unexpected;
  • A three-day field alert report for certain problems, such as significant changes or deterioration, with a drug in distribution. Reporters must submit this information to the applicable FDA district office by telephone or other rapid communication means with prompt written followup. Reporters must maintain a record of the report; and
  • An expedited blood fatality report of a complication of blood collection or transfusion confirmed to be fatal. The report must be submitted by telephone, fax, express mail or electronically, followed by a written report within seven days of the fatality. Reporters must maintain a record of the report.

In some cases, reports made to comply with the product’s approval type would meet the reporting requirements for its constituent part. For example, a reporter submitting a 15-day alert for a serious, unexpected adverse experience associated with the drug part of a drug-device product approved under a PMA also would satisfy the requirement for submission of a 30-day report for a serious device event.

For a combination product approved or cleared under one marketing application, the lead center would have responsibility for review of all postmarketing safety reports. After the lead center receives the postmarketing safety report, it would consult as needed with the other centers.

For products whose components are approved under separate applications, the makers of each component would be subject only to the reporting requirements for its constituent part, the proposed rule says.

Manufacturers would have to submit information about events to the FDA or reporters for the other parts within five calendar days of receiving information about the event. The other reporters would investigate and report the event as required to meet postmarketing safety reporting rules for their constituent parts.

The proposed postmarketing rule does not affect annual or periodic reporting timeframes or the FDA’s authority to require additional postmarketing safety reporting for a particular product.

It also would not apply to device distributors who do not package or otherwise change the container, wrapper or labeling. Device distributors are required to maintain records of incidents but not to report to the FDA. Importers are subject to the rule, the agency says.

The rule, scheduled to be published Oct. 1 in the Federal Register, is part of the FDA’s efforts to clarify requirements for combination products. To date, the agency had not issued regulations on postmarketing safety reporting specifically for them. It has, however, recently issued a proposed rule for good manufacturing practices for such products (DID, Sept. 24).

The FDA is developing an internal electronic infrastructure for combination product safety reports, the postmarketing rule notes. It anticipates implementation prior to the effective date of any final rule.

Comments are due Oct. 31. The proposed rule is available at www.fdanews.com/ext/files/2009-23519_PI.pdf. — April Hollis


FDA Launches Proprietary Name Pilot Program

Drugmakers now may sign up for a new FDA pilot program designed to prevent medication errors caused by proprietary names that look and sound alike.

To register, drugmakers should communicate with the appropriate center within FDA and provide the name of a U.S. regulatory contact, the name of the entity conducting proprietary name analysis, the application type and number, the proposed proprietary name and the approximate month for intended submission, the notice scheduled to be published in the Federal Register Oct. 1 says.

The program is based on a concept paper — “PDUFA Pilot Project Proprietary Name Review” — the agency released last October that explains how firms can evaluate proposed proprietary names at the IND phase or when they submit NDAs, BLAs or ANDAs (DID, Oct. 7, 2008).

Once an applicant is registered in the program, it should send a proprietary name to the FDA within the first two business days of the agreed upon month for the submission. The first page of this submission should include the statement “Request for Proprietary Name Review” and should be immediately followed by the header “Pilot Program.” Both statements should be in bold, capital letters, the notice says.

Applicants should then separate the data in their submission into two separate sections to enable the FDA to conduct parallel reviews, the notice says. The first section should be labeled “Traditional Review” and should contain the proposed proprietary name information that is submitted under the FDA’s traditional practice. The second section should be labeled “Pilot Review” and should contain the comprehensive evaluation of the proposed proprietary name.

The FDA will review submitted names using the Phonetic Orthographic Computer Analysis software program and other tools detailed in a draft guidance titled “Contents of a Complete Submission for the Evaluation of Proprietary Names” issued last November (DID, Nov. 24, 2008).

The agency will accept no more than an average of one to two submissions each month, the FDA says in a notice. It wants to include companies of all sizes and hopes that 25 to 50 proposed proprietary name submissions will be reviewed before the program ends in 2011.

Submissions for a proprietary name related to a new drug or biologic will be reviewed within 90 days, the notice says, and within 180 days for an IND.

The Federal Register notice can be found at www.fdanews.com/ext/files/2009-23620_PI.pdf. The concept paper is available at www.fdanews.com/ext/files/Concept-Paper-Proprietary-Name.pdf. The draft guidance is available at www.fdanews.com/ext/files/Draft-Guidance-Proprietary-Names.pdf. — David Belian


India Centralizes Approval Process for Drug Applications

Drugmakers seeking marketing authorization in India must be inspected by and get approval from the Central Drugs Standard Control Organization (CDSCO) starting Oct. 1 for compliance with the World Health Organization’s good manufacturing practices.

Under the new policy, a zonal or subzonal officer on behalf of the country’s drugs controller general will grant a certificate of pharmaceutical product (COPP) after inspection and satisfactory clearance by officers from CDSCO, the agency says in a document posted on its website.

COPPs already held by manufacturers will remain valid until their expiration date, CDSCO says. The agency has not decided whether to charge application fees to manufacturers, but none will be charged until a decision is made, it says.

Sponsors should send applications to the deputy drugs controller or assistant drugs controller of the applicable zonal or subzonal office, CDSCO says. A copy of the covering letter and product summary sheet should be sent to the drugs controller general’s office.

Applications sent to CDSCO also should be accompanied by a list of products for which they are being sought, as well as a copy of the manufacturing license, notarized product summary sheet and site master file.

According to CDSCO, drugmakers seeking a COPP also should submit:

  • A list of master documents, including a master validation plan, quality manuals, specifications, master formula records and a list of standard operating procedures;
  • A manufacturing layout;
  • Schematics of heating, ventilation and air conditioning, details of areas and schematic diagrams of water systems;
  • A list of personnel, equipment, instruments and utilities with their makes and models; and
  • A list of primary and secondary impurity and reference standards relevant to the products in the application.

The CDSCO regulations on applying for a COPP can be found at www.cdsco.nic.in/madalities_of_COPP.pdf. — David Belian

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