REMS

Analysis and overview of new drug reviews from 1993 through present by an over 20-year-active FDA veteran of drug approvals, Dr. John Jenkins (Director, Office of New Drugs, Center for Drug Evaluation and Research).  The presentation includes review times and comparison to global approvals.  Of note, median approval times for New Molecular Entities (NME) applications are 10 months, a 47% reduction from calendar year 1993.  A status update on CDER compliance with past PDUFA goals is given, with information on forward planning to comply with PDUFA V goals.  In accordance with the enhanced emphasis on benefit-risk analysis in PDUFA V, discussion of the anticipated framework and balance of stakeholder concerns is detailed.   The PDUFA V program for NME review is presented, with key elements and projected timelines detailed.

This slide presentation gives excellent perspective of past and future trends for the global pharmaceutical market, with emphasis on FDA approvals of NME.

Source Slide Show (pdf hyperlink):  FDA

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An Institute of Medicine (IOM) committee report, recommends that the FDA take proactive steps to continue monitoring drug safety after initial approval and throughout the market lifecycle.   Post-market evidence is far greater than what the FDA has when deciding upon initial approval.  The IOM recommendation is that the initial approval is viewed as just one early step in a process that requires continuous, long-term monitoring (the “lifecycle approach”).  The report makes recommendations about how post-market research should be conducted.  The committee found that while randomized controlled trials remain the gold standard for studying drug effectiveness, observational studies have ethical and practical benefits over clinical trials post-approval.  Safety results can be obtained more quickly, therefore regulatory action can be initiated earlier.  One of the key report recommendations is that upon approval, each drug will have a single, publicly available Benefit and Risk Assessment Management Plan (BRAMP) to serve as a central, evolving repository of side effects and other information.  As a centralized comprehensive record, the BRAMP will include a description, a benefit/risk assessment of any safety questions that exist when a drug is approved as well as any that emerge over the course of its market lifecycle, and details on any regulatory actions taken and their results.  Furthermore, it was recommended that the FDA’s drug surveillance systems could be improved through use of various technological and methodological advances (e.g., use of natural language processing for review of electronic medical records).  The possibility was also raised that with a more robust post-approval monitoring process, the more flexible regulatory authorities could be in the pre-approval stage.

SourceMedical News Today, and HealthCanal.com

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FDA Changes Expected with PDUFA V

Posted by cdavenport on Monday Oct 24, 2011 Under FDA, Regulatory

The average cost of developing a drug was $1.3 billion as of January 2011.  The average first-cycle approval rate for standard new molecular entities (NME) has increased from an average of 30% in 1992 to 38% this year.  Priority NMEs have fared better with the FDA, with approvals rising from 46% to 68% during this same period.

The Food and Drug Administration Amendments Act (FDAAA) of 2007, which allowed FDA to require post-marketing studies and clinical trials to address outstanding drug safety questions, lowered the percentage of new drugs, biologics, and efficacy supplements approved by the FDA to below 80% in 2Q 2009.  By 1Q 2011, that percentage returned to the mid 90% range, about the same as in 1Q 2005.

The current forth authorization of the Prescription Drug User Fee Act (PDUFA IV) expires at the end of September 2012.  According to the Draft Commitment Letter signed by the Federal Drug Administration (FDA), Biotechnology Industry Organization (BIO), and Pharmaceutical Research and Manufacturers of America (PhRMA),  to increase the chances of successful first-cycle approvals, PDUFA V will delay the start of FDA’s clock for its first review cycle to after its 60-day administrative filing review period.  Once the clock starts, however, FDA is committed to reviewing and acting on 90% of standard NME, New Drug Application (NDA), and original Biologics License Application (BLA) submissions within 10 months —12 months from the date of filing.  FDA has also committed to reviewing 90% of priority NME, NDA, and original BLA submissions within 6 months, or 8 months from the filing date.  Furthermore, once the PDUFA V review clock starts running, drug developers and FDA officials must meet 3 times:

•    A pre-submission meeting at which “the applicant is strongly encouraged to discuss the planned content of the application.”

•    A new mid-cycle meeting, to which the FDA will call an applicant, will generally be held within 2 weeks after the Agency holds its own internal mid-cycle review meeting on an application.

•    A late-cycle meeting at which FDA’s review team will meet with an applicant to discuss the status of Agency review of the application late in the review cycle.

The new mid-cycle review meeting is meant to provide an opportunity for the Sponsor and Agency to discuss what issues have been identified and how to resolve those issues.  It also provides an earlier opportunity for the Agency to alert the Sponsor if additional information is needed related to labeling, Risk Evaluation and Mitigation Strategies (REMS), and post-marketing commitments.

PDUFA V raises to $3 billion the amount of user fees to be collected by the Agency from a Sponsor.  User fees of $2.9 billion are required by PDUFA IV.  This user-fee increase will enable the Agency to hire additional staff to review drug and biologic applications.  PDUFA V also commits the FDA to develop staff capacity to review submissions that involve pharmacogenomics and biomarkers and to fund the FDA regulatory science initiatives.  To this end, target dates for completion of new initiatives have been set.

  • Oct. 24, 2011: FDA will hold a public meeting to discuss PDUFA reauthorization.
  • Sept. 30, 2013: FDA will develop a dedicated drug development communication and training staff within the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER), and increase the existing manufacturers’ assistance staff at FDA’s Center for Biologics Evaluation and Research (CBER).   The CDER Rare Disease Program within OND will increase the number of staff focused on rare disease drug reviews, which is particularly important due to the increasing emphasis placed by Big Pharma on orphan drugs.
  • Sept. 30, 2014: OND drug development and communication staff will provide training to all CDER staff involved in review of Investigational New Drug (IND) applications.
  • March 31, 2015: FDA will publish draft guidance for review staff and industry describing best practices for communication between FDA and IND sponsors during drug development.

And finally in regards to drug safety and as an effort to lessen the effect of politically-induced risk aversion by the Agency, PDUFA V also calls for greater integration of patient perspectives into the review criteria.  The Agency has explicit plans over the course of the PDUFA V period to change the way it assesses benefits and risks, as well as the endpoints used to assess safety and efficacy, based on the advice it receives from patients.

Sources: Genetic Engineering and Biotechnology News, BioPortfolio, BioCentury, Legal News Directory, FDA

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In the FDA’s effort to make both its decisions and clinical trial data more transparent to the public, Agency decisions have become more available for public debate.  Sophisticated analyses (increasingly by third parties) of publically available data may present to the FDA a more complex picture of drug safety, as not all posted clinical trials fit standard regulatory paradigms, are sufficiently powered, have similar patient selection criteria,  or collect and analyze similar parameters. Changes made in the interest of public health, therefore, may further complicate regulatory assessment of potential changes to drug status.  For these reasons, among others, drug safety decisions are rarely “black and white.”  To its credit, the “new” FDA seems more open to try a middle path (e.g., the diabetes medicine Avandia will remain on the market under a restricted access program [risk evaluation and mitigation strategy, or REMS]).  Even more unusual, however, was public admission by the FDA of disagreement about Avandia within its own scientific ranks.  Furthermore, 3 top FDA officials co-authored a New England Journal of Medicine article explaining their rationale.  Interpretation of clinical trial data, however, is relatively easy compared to analyses of post-market safety data, where patient populations and indications are even more diverse.  It will be interesting to see how public access to evolving data (e.g., the anticipated FDA post-marketing drug safety (public) website) will affect Agency decisions, the timing of those decisions, and how much influence third-party analyses will have on regulatory outcomes.  The upside to the ensuing debate may be heightened public awareness of the importance of risk management, as all drugs have risk.  With the down-spiral of new drugs both coming to and remaining on the market, an outstanding question is whether the public and subsequently the regulatory environment will become more or less risk adverse as our perception of drug safety and risk management evolves.

Source: The New York Times

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Although the Food and Drug Administration (FDA) routinely reviews the safety and effectiveness of all prescription drugs prior to approval, some side effects become evident only after the drugs are taken by millions of patients – far more than it is possible to test in clinical trials.  A drug’s side-effect profile becomes better characterized, therefore, with greater exposure and use.  Additionally, once marketed, many drugs are prescribed for alternate disease states with new target populations; unanticipated safety issues may arise in new target populations.  For this reason, the new on-line quarterly reports (launched 15 June 2010) will  address safety risks that were not identified during a drug’s development or prior to FDA approval.  These reports are targeted to appear within roughly 2 years of a new drug’s approval (back to 27 September 2007) or, for drugs that have Risk Evaluation and Mitigation Strategies (REMS), since the REMS was required or last assessed.  REMS ensure that the benefits of a drug or biological product outweigh its risks.

Quarterly safety summaries incorporate potential signals of serious risks/new safety information identified by the Adverse Event Reporting System (AERS) as well as by FDA-initiated research.  When a potential signal of a serious risk is identified from AERS data, it is entered as a safety issue into the Center for Drug Evaluation and Research (CDER) Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) or into the Center for Biologics Evaluation and Research (CBER) Therapeutics and Blood Safety Branch Safety Signal Tracking (SST) system.  Although potential signals of serious risks are usually based upon groups of AERS reports, a single AERS report could initiate the evaluation of a potential safety issue.  FDA posts each potential signal of a serious risk in the quarter in which it is first identified.  If additional safety information is developed concerning a potential signal that has already been posted, it is addressed by FDA in new safety communications/updates, but does not appear again as a new quarterly posting.  Listing does not necessarily imply a causal relationship between the drug and the identified risk.  The FDA is requiring REMS formulation as well as posting of  quarterly drug safety reports in accordance with Title IX, Section 921 of the FDA Amendments Act (FDAAA) of 2007 (see insert).

Source: The Herald Sun

Relevant References: Mass Tort Defense,  FDA Law Blog, FDA Transparency Blog

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James N. Czaban (FDA Practice Group, Wiley Rein LLP) discusses trending topics of the FDA in regard to drug safety.  A perception exists that the FDA does far more in terms of actual product testing and oversight than it is actually authorized to do, which can result in overconfidence in the safety of the nation’s drug and food supplies.  Misguided outrage is often directed at the FDA, therefore, when a high-profile food or drug safety crisis arises.  Others, however, perceive that the Agency has been too aggressive in regulating industry, especially with regard to the lengthy  drug approval process, advertising and promotional oversight, and in restricting access to investigational new drugs and dietary supplements.  Under President Obama, therefore, the new FDA leadership has placed very visible emphasis on the heightened enforcement and compliance activity of regulated industries.

An important Supreme Court decision in 2009 was Wyeth v. Levine.  In that case, the question considered by the Court was whether FDA labeling requirements preempted decisions by state courts regarding adequate labeling.  The Supreme Court held that there was no preemption.  This puts drug makers in an untenable position of having to guess what a jury might decide is required in a drug label, while at the same time being restricted by FDA in what changes they can make to the label.

In 2010 continued emphasis on enforcement of drug and food safety by the FDA is anticipated.  In regard to Risk Evaluation and Mitigation Strategies (REMS), which were authorized by the FDA Amendments Act of 2007, it is unknown whether the FDA can achieve a REMS policy that strikes an appropriate balance between enhanced safety and prompt patient access to new therapeutics.   In addition, many issues are outstanding regarding the development of guidelines for follow-on biologics; this includes determination of the length of marketing exclusivity to be given to the original innovator versions of such products.   Other FDA trends are discussed.

Source: Metropolitan Corporate Counsel

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Evolving FDA and EMEA Collaborations

Posted by cdavenport on Monday Jan 11, 2010 Under Drug Safety, EMEA, FDA

Collaboration between the 2 of the world’s premier pharmaceutical regulatory bodies (FDA and EMEA) has increased markedly in the last few years, a process which has come largely in response to the rapid globalization of drug development, manufacturing, and production.  Distillation of an interview with Murray Lumpkin, the FDA’s Deputy Commissioner for International Programs who is spearheading the FDA’s efforts in this field, gave several succinct insights relative to the history and context of the collaboration and drug safety (preclinical and clinical) initiatives, among others.

Over the past 10-15 years, the FDA and EMEA initially focused on understanding each other’s regulatory systems.  This initiative evolved to  sharing  information (managerial and technical) since pharmaceutical companies were  submitting largely similar information to both Agencies.  The “Transatlantic Administrative Simplification Action Plan,”  a centerpiece of this relationship,  covers 4 primary areas of potential convergence: 1) quality and inspections, 2) pharmacovigilance, 3) scientific collaboration, and 4) guidelines, format harmonization,  and electronic submission.  Information is shared about applications,  questions and answers, and pre-decisional information.  Drafts of guidance and policy documents are also shared prior to publication.  We try to give each other a heads up on newsworthy items and/or something that is likely to generate questions for them.  We don’t want to blindside each other, particularly in regard to issues with a public health or safety impact.  This cooperation has led to the permanent placement of an executive in each other’s organization:  Janice Soreth (from FDA) and Hilde Boone (from EMEA).

FDA/EMEA “clusters”  in pediatrics and oncology have been particularly active, with periodic teleconferences detailing current applications and upcoming actions, challenges and difficult questions, and various meeting updates (sometimes with joint participation).  Although resolutions may differ between Agencies, there is a mutual understanding of how decisions were formulated, and an acknowledgment that similar data was evaluated by both.  Other examples of joint clusters include:  vaccines, pharmacogenomics, orphan medicines, and cardiovascular.

The potential for joint acceptance of each other’s drug approvals was discussed.  It was acknowledged that although regulatory decisions are largely science based, there are also jurisdictional componenets, such as risk tolerance, which remain largely cultural.  For this reason, mutual acceptance of drug approvals was not seen as likely in the near term.

Upcoming prospects for convergence may involve leveraging each other’s resources (e.g., GMP and GCP inspections) to reduce audit duplication.  The distinction was made that this effort would enable the Agencies to rely on each other’s information, but not necessarily on each other’s decisions.  Other areas of possible harmonization may include biomarkers (e.g., the recent joint validation of renal toxicity biomarkers), as well as trial design and comparators.  In regard to drug safety, the pharmaceutical industry has been invited to conduct a study to compare the EU and US approaches to risk management formats (e.g., E2E, Volume 9a RMP Guidance, REMS, etc.) and to identify opportunities for convergence.  In addition, other areas for possible convergence were discussed.

Source:  InPharm

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Was the REMS meant to regulate prescribers and pharmacists?

Posted by cdavenport on Sunday Oct 11, 2009 Under Risk Management

As of 2007, the FDA has the  authority to require a Risk Evaluation and Mitigation Strategy (REMS) for certain drugs and biological products, to ensure that the benefits of such products outweighed the risks.  Although the FDA mandated risk-management plan applies only to prescription drugs and biologicals, the effect of a REMS extends down the supply chain to affect which physicians may prescribe and how pharmacies dispense medication, even though the FDA has no regulatory authority beyond manufacturers.  Ned Milenkovich (Modern Medicine, 8 Oct 2009) poses the question, therefore, whether Congress and the FDA are exceeding their authority by indirectly regulating professions that traditionally have been governed by the various states?  This article gives a good overview of the status and use of REMS by the FDA and Industry and considers the indirect effects.

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The U.S. Food and Drug Administration announced (30 Sept 2009) the availability of the first draft guidance for industry on Risk Evaluation and Mitigation Strategies (REMS), which are required for certain drugs or biologics.

The Food and Drug Administration Amendments Act of 2007 (FDAAA) granted the FDA the authority to require the submission and implementation of a REMS if the FDA determines that a REMS is necessary to ensure that a drug’s benefit outweighs its risks.

An approved REMS that is voluntarily submitted is subject to the same requirements and enforcement as a REMS that was originally submitted as a required proposed REMS.  If an applicant voluntarily submits a proposed REMS, it will not be approved as a REMS until the FDA determines that it is required to ensure that the benefits of the drug outweigh the risks and that it meets the FDAAA criteria.  Proposed REMS that are not approved are not subject to the requirements and enforcement of an approved REMS.  FDA will notify applicants who voluntarily submit a proposed REMS whether the REMS will be required.  If the FDA determines that a REMS is not required, an applicant may undertake voluntary risk management measures that would be performed outside of a REMS.

Differentiation between a REMS and the earlier (i.e., prior to FDAAA) risk minimization action plans (RiskMAPs) is addressed.

Source: FDA Draft Guidance

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