Letters

Annals of Internal Medicine COMMENTS

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RESPONSES

References 1. Kesselheim AS, Bykov K, Avorn J, Tong A, Doherty M, Choudhry NK. Burden of changes in pill appearance for patients receiving generic cardiovascular medications

Burden of Changes in Generic Pill Appearance

after myocardial infarction: cohort and nested case–control studies. Ann Intern Med. 2014;161:96-103. [PMID: 25023248] doi:10.7326/M13-2381

TO THE EDITOR: There are many reasons for patient nonadherence

2. U.S. Food and Drug Administration. Guidance for Industry: Size, Shape,

to a prescribed therapeutic regimen. Kesselheim and colleagues (1) identify an important contributor: variability in the appearance (for example, shape, color, and size) of tablets. We realize that changes in pill appearance and packaging can contribute to patient nonadherence, and the U.S. Food and Drug Administration (FDA) has published draft guidance addressing certain aspects of these concerns (2– 4). Because generic drugs currently represent nearly 85% of prescriptions dispensed, patients will continue to experience changes in pill appearance as economic forces lead to product turnover in pharmacies and mail-order houses. These points of distribution may not carry the same manufacturer’s generic product between the time of initial dispensing and refill. In addition, appearance changes are not just an issue with generic drugs; brand-name drugs sometimes have postapproval manufacturing changes that affect patient acceptance. For example, in 2007, Dilantin (Pfizer) was changed from a white capsule with a red stripe to a larger white capsule with orange on 1 end. After this change, reports of breakthrough seizures increased. The legal protections for characteristics of drug products known as “trade dress” are extensive. Even color can constitute a defensible trademark. Greene and Kesselheim (5) have previously reviewed this issue for interchangeable generic drugs. Given the broad protections for many aspects of the physical characteristics of a branded drug, an FDA requirement that a generic drug have the same or a similar size, shape, and color as the reference drug could effectively eliminate the ability to market a generic product in many cases, thus restricting or limiting patient access to more affordable medicines. The FDA has become more sophisticated in providing protocols and methods that ensure bioequivalence of generic products. We recognize the importance of the physical characteristics of drugs and packaging as factors in a patient’s smooth transition from a brandname to a generic drug and from one generic drug to another. Short of substantial changes in the legal protections for trade dress and trademark, the FDA has 2 options to address the issue: advise manufacturers through guidance documents, and survey the approved generic products to identify any potential failure of therapeutic effect or change in risk profile relative to the branded reference drug. We note that the authors have received FDA funding to investigate the social science aspects of the very issue raised in their article. The FDA has worked within the limits of its legal authority to use both of these options to ensure the continued safety, efficacy, and substitutability of bioequivalent products for the public. Differing pill appearances confuse patients and physicians. The dispensing pharmacist currently is responsible for explaining these differences to concerned patients.

and Other Physical Attributes of Generic Tablets and Capsules: Draft Guidance.

Kathleen Uhl, MD John R. Peters, MD Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration Silver Spring, Maryland

be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0453.

Silver Spring, MD: U.S. Food and Drug Administration; 2013. Accessed at www .fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances /UCM377938.pdf on 28 October 2014. 3. U.S. Food and Drug Administration. Guidance for Industry: Safety Considerations for Product Design to Minimize Medication Errors: Draft Guidance. Silver Spring, MD: U.S. Food and Drug Administration; 2012. Accessed at www.fda.gov/Drugs /GuidanceComplianceRegulatoryInformation/Guidances/ucm331808.htm on 28 October 2014. 4. U.S. Food and Drug Administration. Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors: Draft Guidance. Silver Spring, MD: U.S. Food and Drug Administration; 2013. Accessed at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation /Guidances/UCM349009.pdf on 28 October 2014. 5. Greene JA, Kesselheim AS. Why do the same drugs look different? Pills, trade dress, and public health. N Engl J Med. 2011;365:83-9. [PMID: 21732842] doi:10.1056 /NEJMhle1101722

TO THE EDITOR: Kesselheim and colleagues (1) provide data on the

burden of changes in the appearance of generic drugs in terms of patients’ discontinuing their generic medications. Although this is an important finding, it is only the tip of the iceberg of the risk associated with generic medications. As a caregiver for my elderly mother and as a patient—with both my mother and me having a suite of chronic conditions that require multiple medications—I believe that a far greater problem is that changes in the appearance of generic pills greatly increase the likelihood of medication errors. Although all medications are neatly delivered in labeled but difficult-to-open containers, they are often decanted into 1-day-perweek pillboxes for convenience and to enhance adherence. As such, patients with limited vision often rely on shape, size, and color to distinguish among their pills. Changing appearance can cause confusion and errors. Even generic medications are regulated by the FDA in terms of purity, strength, and potency. I believe no reason exists why such regulation cannot be extended to a pill’s appearance. This is an issue of patient safety that warrants immediate attention. Stephen Pauker, MD Tufts Medical Center Boston, Massachusetts Disclosures: Authors have disclosed no conflicts of interest. Forms can

Reference 1. Kesselheim AS, Bykov K, Avorn J, Tong A, Doherty M, Choudhry NK. Burden of

Disclosures: Authors have disclosed no conflicts of interest. Forms can

changes in pill appearance for patients receiving generic cardiovascular medications

be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0452.

after myocardial infarction: cohort and nested case–control studies. Ann Intern Med. 2014;161:96-103. [PMID: 25023248] doi:10.7326/M13-2381 © 2014 American College of Physicians 839

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Letters IN RESPONSE: We believe that Drs. Uhl and Peters’ perception that

brand-name manufacturers could successfully claim monopoly protection for the appearance of their pills as “trade dress” is not supported by current intellectual property law. Since a key 1982 decision, the U.S. Supreme Court has stated many times that no valid trade-dress rights can exist in a feature of a product that is functional, which is defined as something that is “essential to the use or purpose of the article or . . . affects the cost or quality of the article”(1). In 1998, the U.S. Trademark Act was amended to expressly prohibit registration any of “matter that, as a whole, is functional” (2). In 1 relevant case, the court ruled that the pink color of wall insulation was nonessential to the product’s use (3). By contrast, the black color of a motorboat engine was found to be functional because it allowed easier coordination with other boat colors and reduced the apparent size of the engine to customers (4). The data from our studies, combined with statements from patients, such physicians as Dr. Pauker, and other reports in the literature, provide substantial evidence of the important function of a consistent appearance of pills among otherwise interchangeable drug products in promoting adherence and reducing patients’ errors. Applying this standard, a federal appeals court in 2003 struck down the prospect of trade-dress rights for the shape and color of a tablet form of amphetamine– dextroamphetamine (Adderall, Shire) on the grounds that “similarity in tablet appearance enhances patient safety by promoting psychological acceptance” (5). Drs. Uhl and Peters’ letter reveals the FDA’s position that bioequivalent generic drugs that look like their brand-name counterparts enhance patient acceptance and improve clinical outcomes. Because courts routinely defer to the FDA’s authority in ensuring the safety and efficacy of prescription drugs, this agency could formally acknowledge this position in a guidance document. Such a move would not impose absolute obligations on generic manufacturers to produce identical-looking drugs or preclude brand-name manufacturers from asserting legal claims to trade-dress rights in those features, even if those claims were unlikely to succeed. However, such guidance would be useful by providing important factual input that could guide courts’ subsequent deliberations about whether the appearance feature for which trade-dress protection is sought is functional—and therefore unprotectable. Aaron S. Kesselheim, MD, JD Niteesh K. Choudhry, MD, PhD Jerry Avorn, MD Brigham and Women’s Hospital Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org/authors

/icmje/ConflictOfInterestForms.do?msNum⫽M13-2381.

References 1. Inwood Labs, Inc., v. Ives Labs, 456 U.S. 844 (1982). 2. Trademark Act, 15 U.S.C. §1052(e)(5) (2013).

Instrumental Variable Analyses for Observational Comparative Effectiveness Research: The Paired Availability Design TO THE EDITOR: Garabedian and colleagues’ article (1) discusses

potential bias in the instrumental variable analysis of observational studies. However, it did not mention an important type of instrumental variable approach for use with observational data, namely, the paired availability design (PAD) (2– 4). Under the PAD, time period is the instrumental variable and the availability of new treatment for patients changes over time periods. The PAD makes a key assumption that Garabedian and colleagues discuss: that the instrument affects the outcome only through treatment. The PAD also assumes stable preferences, namely, that treatment preferences do not change over time. For a fixed increase in time of availability in one period versus another, the stable preference assumption implies that the effect of treatment is always in the same direction, another key assumption that Garabedian and colleagues discuss. For a randomly occurring increase in time of availability in one period versus another, the stable preference assumption implies a certain type of randomness in the direction of treatment that yields an identical estimate of treatment effect as under a fixed increase in time of availability (4). Because the PAD does not involve an adjustment for baseline variables, it has the advantage of simplifying data collection. However, investigators must then be careful to reduce bias in the study design. The key potential bias is that time may affect the outcome directly and not through treatment. To mitigate the potential for this bias, we recommend using short periods, keeping staff and all other aspects of patient management constant over time, and analyzing only geographically or institutionally isolated medical centers (which reduces the possibility of temporal changes in the demographic characteristics of the eligible population). The use of multiple medical centers averages the effect of random changes over time. In 1994, we introduced the PAD with a proposed study of the effect of epidural analgesia on the probability of cesarean delivery (2). After data became available, we compared the results of the PAD with those from a meta-analysis of randomized trials and a multivariate adjustment for possible confounders (4). Despite the aforementioned potential biases, our application of the PAD to obstetric data gave results that were qualitatively similar to those of the metaanalysis of randomized trials but substantially different from those using the multivariate adjustment. We believe that the omission of a key unmeasured confounder biased the multivariate adjustment. All methods of analyzing observational data require assumption. In some applications, we believe that the PAD offers more reasonable assumptions (and hence less possibility of bias) than other methods. Stuart G. Baker, ScD National Institutes of Health Bethesda, Maryland Karen S. Lindeman, MD Johns Hopkins Medicine Baltimore, Maryland

3. In re Owens Corning Fiberglas Corp. , 774 F.2d 1116, 1128 (Fed. Cir. 1985). 4. Brunswick Corp. v. British Seagull Ltd., 35 F.3d 1527 (Fed. Cir. 1994).

Disclosures: Authors have disclosed no conflicts of interest. Forms can

5. Engelberg AB. The case for standardizing the appearance of bioequivalent medica-

be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0460.

tions. J Manag Care Pharm. 2011;17:321-3. [PMID: 21534643] 840 2 December 2014 Annals of Internal Medicine Volume 161 • Number 11

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Letters References 1. Garabedian LF, Chu P, Toh S, Zaslavsky AM, Soumerai SB. Potential bias of instrumental variable analyses for observational comparative effectiveness research. Ann Intern Med. 2014;161:131-8. [PMID: 25023252] doi:10.7326/M13-1887 2. Baker SG, Lindeman KS. The paired availability design: a proposal for evaluating epidural analgesia during labor. Stat Med. 1994;13:2269-78. [PMID: 7846425] 3. Baker SG, Lindeman KS, Kramer BS. The paired availability design for historical controls. BMC Med Res Methodol. 2001;1:9. [PMID: 11602018] 4. Baker SG, Lindeman KS. Revisiting a discrepant result: a propensity score analysis, the paired availability design for historical controls, and a meta-analysis of randomized trials. J Causal Inference. 2013;1:51-82.

IN RESPONSE: Drs. Baker and Lindeman question our omission of

time period as a potential instrumental variable for comparative effectiveness research. Our study focused on the 4 most commonly used instruments in this research. However, we did acknowledge the potential for time-based instruments by stating, “The assumption that the instrument is only related to the outcome through the treatment may apply best to specific, focused, plausibly exogenous interventions or events, such as natural experiments (for example, the Oregon Medicaid lottery [1] or changes in policy or technology [2]).” The PAD studies cited by Drs. Baker and Lindeman did not explicitly use instrumental variable analysis, so they were not included in our review. We agree that the introduction of a medical intervention, technology, or policy change affecting treatment uptake might be a valid instrument. Nonetheless, such analyses rely on key assumptions— many of which Drs. Baker and Lindeman consider in their PAD studies—that often are not satisfied in practice (3, 4). In particular, changes in patient characteristics or other aspects of treatment that occur at the same time as the treatment of interest could be instrument– outcome confounders and bias the instrumental variable estimate. A truly exogenous and isolated policy satisfies these assumptions (2, 4). Similarly, a randomized instrument, such as the Oregon Medicaid lottery (1), protects against instrument– outcome confounding. However, policy changes and randomized encouragement instruments may be weak predictors of the treatment if they do not sufficiently change provider or patient behavior. A weak instrument will inflate any residual bias (4). In addition, time-based instrumental variable analyses, including the PAD, rely on a weak pre–post research design. This method does not account for trends that may bias results and is particularly problematic for interventions that manifest over long periods. Interrupted time-series methods have been developed to account for many biases that plague temporally identified interventions (5) and may be more appropriate than instrumental variable analyses. Laura Faden Garabedian, PhD Alan M. Zaslavsky, PhD Stephen B. Soumerai, ScD Harvard Medical School and Harvard Pilgrim Health Care Institute Boston, Massachusetts

ical outcomes. N Engl J Med. 2013;368:1713-22. [PMID: 23635051] doi:10.1056 /NEJMsa1212321 2. Angrist JD, Krueger AB. Instrumental variables and the search for identification: from supply and demand to natural experiments. J Econ Perspect. 2001;15:69-85. 3. Baker SG, Lindeman KS, Kramer BS. The paired availability design for historical controls. BMC Med Res Methodol. 2001;1:9. [PMID: 11602018] 4. Brookhart MA, Rassen JA, Schneeweiss S. Instrumental variable methods in comparative safety and effectiveness research. Pharmacoepidemiol Drug Saf. 2010;19:53754. [PMID: 20354968] doi:10.1002/pds.1908 5. Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27:299-309. [PMID: 12174032]

Responding to Measles in the Postelimination Era TO THE EDITOR: Sammons (1) provides a timely reminder of the

importance of case recognition and management of measles given the ongoing international outbreaks of this condition and repeated introductions of infectious measles cases into the United States that trigger outbreaks, but several additional points deserve mention. As Sammons rightly points out, clinicians must be able to promptly recognize classic clinical cases of measles on the basis of symptoms, signs, and travel and exposure history. It is also important to note that reexposure to measles among those with preexisting immunity, including previously vaccinated persons (particularly health care workers [HCWs]) and those from measles-endemic countries who have already had measles, can lead to a modified clinical illness that may not initially be recognized as measles (2). Obtaining specimens for measles RNA testing is especially important in these cases because interpretation of serologic tests can be difficult. Sammons also states that airborne precautions should be used for hospitalized patients with measles but that current guidelines do not specify whether a surgical mask or particulate respirator is indicated. Although the current guideline from the Healthcare Infection Control Practices Advisory Committee (3) is agnostic on this point, more recent guidance from the Centers for Disease Control and Prevention is clear that, irrespective of vaccination history, HCWs entering the rooms of patients with suspected or confirmed measles should use an N95 or similarly protective respirator (4). Assuring and documenting that all HCWs have had 2 doses of measles, mumps, and rubella vaccine minimizes the risk for infection and facilitates efficient management of HCWs exposed to patients with measles. Finally, in my experience, disproportionate importance is placed on the finding of Koplik spots in the assessment of potential measles cases. A report of these spots is understandably not very reliable given most physicians’ general lack of familiarity with acute measles cases. More troubling is the tendency to erroneously interpret the absence of the pathognomonic spots as evidence against acute measles infection.

Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-1887.

Jeffrey S. Duchin, MD Public Health—Seattle and King County and University of Washington Seattle, Washington

References

Disclosures: Authors have disclosed no conflicts of interest. Forms can

1. Baicker K, Taubman SL, Allen HL, Bernstein M, Gruber JH, Newhouse JP, et al; Oregon Health Study Group. The Oregon experiment—effects of Medicaid on clin-

be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0448.

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Letters References 1. Sammons JS. Ready or not: responding to measles in the postelimination era. Ann Intern Med. 2014;161:145-6. [PMID: 24763975] doi:10.7326/M14-0892 2. Rota JS, Hickman CJ, Sowers SB, Rota PA, Mercader S, Bellini WJ. Two case studies of modified measles in vaccinated physicians exposed to primary measles cases: high risk of infection but low risk of transmission. J Infect Dis. 2011;204 Suppl 1:S559-63. [PMID: 21666213] doi:10.1093/infdis/jir098 3. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control Practices Advisory Committee. 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings. Atlanta, GA: Centers for Disease Control and Prevention; 2007. Accessed at www.cdc.gov/hicpac/pdf/isolation /isolation2007.pdf on 28 October 2014. 4. Advisory Committee on Immunization Practices. Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60:1-45. [PMID: 22108587]

IN RESPONSE: I appreciate Dr. Duchin’s expansion on some of the

nuances in measles recognition. It is true that clinical presentations may vary in those who have been previously vaccinated. Immunocompromised patients may also present with a modified clinical picture. In addition, I agree that the absence of Koplik spots should not exclude measles from the differential diagnosis of a patient who has other relevant clinical features and an appropriate exposure history, particularly because these spots are transient, lasting between 2 and 3 days. Still, for providers who have never seen measles, the critical first step is awareness and the consideration of measles in returned travelers with febrile rash illness. The importance of appropriate isolation and use of airborne precautions for suspected and confirmed cases of measles cannot be overemphasized. Dr. Duchin correctly points out recent guidance from the Advisory Committee on Immunization Practices (1) that includes a recommendation for use of an N95 respirator or one with similar effectiveness in preventing airborne transmission. This recommendation will hopefully be incorporated in an updated version of current guidelines for isolation precautions (2). Julia Shaklee Sammons, MD, MSCE Perelman School of Medicine, University of Pennsylvania, and The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Disclosures: Authors have disclosed no conflicts of interest. Forms can

be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽M14-0892. References 1. Advisory Committee on Immunization Practices. Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60:1-45. [PMID: 22108587] 2. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Health Care Infection Control Practices Advisory Committee. 2007 guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control. 2007;35: S65-164. [PMID: 18068815]

The Challenge of Deadopting Low-Value Care TO THE EDITOR: I read Drs. Roman and Asch’s essay (1) with great interest and wish to share my perspective on runaway health care costs and their sources within the internal medicine community.

Although psychological forces may be at play in the deadoption of chemotherapeutic agents, procedures, and technologies, I do not believe they are an important factor in causing runaway costs. Rather, the major cause is the pervading culture that emanates from what Dr. Arnold Relman described as the “medical–industrial complex” (2). The American College of Physicians has taken a bold and important initiative with their new emphasis on introducing value training for graduate trainees in internal medicine. Unfortunately, the problem begins in medical schools, where students are seduced by the lures found within the hallowed halls of technology and cutting-edge procedures. I believe that the Hippocratic oath needs to be reworked and updated to include the necessity of always striving to care for patients in the most cost-effective way possible with the goal of providing the “greatest good for the greatest number.” It needs to be emphasized that providing cost-effective and medically appropriate care is as important as having compassion for patients and their families, acquiring the necessary training and expertise, continuing medical education, and being leaders of the health care team. It is imperative that specialists as well as primary care physicians adopt this new perspective. Medical, physician assistant, and nurse practitioner students; interns; residents; and fellows must learn that their mentors and teachers are judging them not only by their ability to properly perform a procedure but also by their having the expertise in clinical decision making to know when and why that procedure is medically appropriate. For example, when I trained in the mid-1980s, it was almost de rigueur to order as many tests as one could think of when working up a patient for an undiagnosed illness. Think of the neurologist who sees an elderly patient with dementia and orders testing for HIV, antinuclear antibodies, and Lyme disease; a rapid plasma reagin test; erythrocyte sedimentation rate measurement; electroencephalography; and magnetic resonance imaging (when computed tomography of the brain has already been done). The public has been brainwashed into thinking that more is better and a sign of caring by the physician when in reality the physician is often motivated by what is best for his or her business and bottom line. Thus, it is no surprise that gynecologists have been able to promote unnecessary annual checkups (including Papanicolaou smears) for years. I will never forget reading in Annals in the late 1980s that, based on our understanding of the natural history of cervical dysplasia, Papanicolaou smears in the average-risk woman can safely be spaced 3 years apart—assuming that the results are normal each time—and then experiencing the real world where women typically received this test annually even when they did not have cervixes. Until the medical community chooses to add “cost-effective care” as one of its core values for all specialties, the United States will continue to lead the world in health care costs per capita. Unfortunately, as we all know, spending the most has not, and never will, translate to providing the highest-quality care. Frederic H. Schwartz, MD University of Massachusetts School of Medicine Worcester, Massachusetts Disclosures: Authors have disclosed no conflicts of interest. Forms can

be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0414.

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Letters References 1. Roman BR, Asch DA. Faded promises: the challenge of deadopting low-value care. Ann Intern Med. 2014;161:149-50. [PMID: 24781317] doi:10.7326/M14-0212 2. Relman AS. The new medical-industrial complex. N Engl J Med. 1980;303:963-70. [PMID: 7412851]

IN RESPONSE: We agree with Dr. Schwartz that high costs have

many origins. However, our main point was that addressing medical overuse will require more than just setting new standards of appropriateness and providing education and guidance to reach those standards. Our difficulty giving up low-value services arises less because physicians might be self-interested or socialized toward the wrong goals and more because physicians are human and susceptible to characteristically human errors in thinking. These include optimism bias, confirmation bias, loss aversion, the affect heuristic, and perhaps other decision processes that are not the products of reason but reflections of our psychological foibles.

MANUSCRIPT PROCESSING

By all means, let’s teach about and socialize our physicians toward economically prudent care and recast professional standards to include value. But unless we also acknowledge and learn to circumvent our deeply seated psychological biases, we shouldn’t expect any of these approaches to get us much closer to our goals. Benjamin R. Roman, MD, MSHP Memorial Sloan Kettering Cancer Center New York, New York David A. Asch, MD, MBA University of Pennsylvania Philadelphia, Pennsylvania Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M14-0212.

AND

TURNAROUND

Annals sends about half of submitted manuscripts for peer review and publishes about 8% of submitted material. The 2013 processing and notification turnaround time for manuscripts that were rejected without external peer review was within 1 week for more than 92% of submitted manuscripts. The processing and notification turnaround time for manuscript that were received and rejected after external peer review was within 4 weeks for 60% and within 8 weeks for 99%.

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