Among the issues leading to the recent resignation of the President of Stanford University was “a frustrating 3-year failed effort by Genentech scientists to replicate the results” of his 2009 paper published in Nature, which seemed to explain the brain degeneration in Alzheimer disease (Kaiser, 2023). Because they could not reproduce the experiments, Genentech ended efforts to develop an Alzheimer treatment on the basis of that work. Although the studies that Genentech scientists could not reproduce were done in Genentech laboratories in this case, it is more common that industry scientists wanting to confirm preclinical mechanistic findings before proceeding with research toward drug development that will cost millions of dollars find that they cannot reproduce published studies performed by university scientists.

The US Food and Drug Administration (FDA) is the federal agency charged with regulating all of our foods, human and veterinary drugs, medical devices, biologics, cosmetics, and tobacco products. Clearly the FDA budget (US$5.1 billion) is too small, with too few employees (17,000) to actively make or supervise all of the decisions affecting 20% of the US product spending. The system therefore depends on a great deal of voluntary self-regulation from the pharmaceutical industry and other regulated industries. It is important to recognize that the laws governing the drug approval process are drafted to meet broad public health and social policy considerations. The regulations developed to implement these laws quickly become complicated and are constantly fine-tuned to meet new circumstances and specific situations. In addition to federal ‘Regulations,’ the FDA also issues ‘Guidances.’ Unlike Regulations, which are legally binding, Guidances represent the FDA's current thinking and recommendations, but are not legally binding.

The 21st Century Cures Act of Dec 31, 2016,1 requires evaluation of the potential use of real-world evidence (RWE) for US Food and Drug Administration (FDA) approval of new indications for already-approved drugs and for fulfilling postapproval requirements. What is RWE and why did Congress and the President direct the FDA to create a “framework and guidance” for evaluating RWE for drug approvals? As yet, the federal government's definition of RWE is not clear. The 21st Century Cures Act defines RWE as evidence “derived from sources other than randomized clinical trials.” However, in its guidance on use of RWE to support regulatory decision making for medical devices, the FDA defined RWE as data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.

Recent changes in US Food and Drug Administration (FDA) approval requirements for cancer and other serious life-threatening diseases have resulted in many new cancer drugs, including drugs for skin cancer. This success suggests that adjusting the requirements for lifedisrupting but nonlethal diseases often treated by dermatologists might also stimulate the development of many new drugs for such conditions. However, the American public and the US Congress are alarmed by the high cost of these new drugs.1,2 For example, the price of anticancer drugs has more than doubled, from $4500/mo to over $10 000/mo over the past 10 years,3 and the 21st Century Cares Act that was recently introduced in the US House of Representatives reflects this concern.4 Although drug prices are not determined only by the cost of drug development, it is one of the important drivers of price and, ultimately, availability. A recent study5 found that developing a new drug takes over a decade and costs approximately $2.6 billion. Nearly half this cost is the so-called capital cost, or the loss of expected returns that are forgone while a drug is in development. Although some of the study methodology is contested,5 there is no doubt that development costs have risen. The number of new drugs approved is thought to be related to the increased cost of development, and while in 2015 there were a record 41 new drugs approved (9 for cancer), over the past decade (through 2014) 25% fewer drugs were approved than in the 1990s.6 Since 1950, the number of drugs approved per billion dollars spent on research and development has halved roughly every 9 years. This decline has been labeled Eroom’s law, or the reverse of Moore’s law7 that describes the doubling every 2 years of chip circuitry efficiency. Among the alleged causes of Eroom’s law are the cautious regulator problem (ie, the tendency for regulators and the public to be more intolerant of risk when treatments already exist) and the better than the Beatles problem (ie, the need for new treatments to be better than those already available). Because the most expensive part of drug development is phase 3, being between 40% and 50% of outof-pocket development cost, reducing the costs of clinical trials would produce considerable savings and hopefully result in more drugs being developed at lower prices. To reduce developmental costs and encourage the development of new drugs to treat life-threatening diseases, current FDA regulations allow approval based on (1) phase 3 studies shortened by using unvalidated surrogate end points when the end point is reasonably likely to predict a real clinical end point and (2) preliminary clinical evidence of superiority over current treatment alongside studies using a pharmacodynamic biomarker end point that does not meet criteria for an acceptable surrogate end point. The ability to use unvalidated surrogate or intermediate end points has led to a large number of drugs aimed at cancers. These new pathways have included expedited reviews of applications such that the approval of cancer-fighting drugs is faster than for drugs targeting other indications.8 When considering broadening the use of unvalidated end points it is important to understand the often unapparent regulatory limitations of biomarkers. Biomarkers, short for biological markers, are physical or laboratory measurements thought to have use for diagnosing or evaluating a disease or condition. Physiologic biomarkers (ie, blood pressure and heart rate) have been used in medicine for many years. However, in medicine, the term has only been commonly applied with the advent of molecular research. Biomarkers are now almost synonymous with molecular markers such as the KRAS and PSA proteins. Clinical end points are determinations of how a person feels, functions, or survives. Biomarkers substituting for clinical outcomes are surrogate markers or surrogate end points. They have the potential to reduce the time and cost of clinical studies. For a biomarker, which is a numeric measure, to be useful for regulatory purposes it should reflect the ultimate clinical end point. However, by their naturebiomarkerswillonlymeasure1elementinapathogenic pathway. Because the test agent may be functioning in 2 or more ways, the biomarker might not assess the full therapeutic effect. The biomarker is even more unlikely to predictadverseoutcomesand/ortoxiceffects. Ithastherefore been suggested that a panel of biomarkers might be needed. Surrogate end points are almost never validated becausevalidatingthatabiomarkerindicatesthefullortrue clinicaloutcomeis likelytorequiremoretimeandcostthan directly studying the clinical outcome of the intervention. Other proposed methods to reduce the cost of drug development include the use of adaptive clinical trials, adaptive randomization, and more efficient animal model screening for first-in-class small molecules. Clearly cost reduction is most likely to be greatest when the techniques affect the clinical development portion of the budget. Accepting studies using unvalidated surrogate end points has led to the availability of many new anticancer drugs. Adopting similar standards for drugs aimed at nonlethal diseases might produce more drugs for these conditions as well. However, anticancer, as well as VIEWPOINT

Clinical trials are critical for the development of new therapies in dermatology, and their results help determine US Food and Drug Administration (FDA) approval and guide care. Of special relevance is the clinical trial efficacy end point, the metric from which statistically significant outcome is derived. Clinicians' understanding of a clinical trial's end point is necessary for critical analysis of the trial results and for applying those results to daily practice. This review provides practical knowledge and critical evaluation of end points used in treatment approvals by the FDA. The end points for actinic keratosis, acne vulgaris, atopic dermatitis, onychomycosis, and cutaneous ulcer serve as examples.

IB methods. It was rather surprising that IIF showed positive reactivity with normal human skin, but not 1 mol L 1 NaClsplit skin, because IIF of 1 mol L 1 NaCl-split skin is usually more sensitive. It is possible that 1 mol L 1 NaCl treatment may mask or destroy the epitopes on the BP180 C-terminal domain or b4 integrin, which was specifically reacted to by the patient serum. It was also unknown why IgA antibodies were detected by IB but not by IIF. IB of the BP180 C-terminal domain recombinant protein may be more sensitive in detecting IgA antibodies than immunofluorescence, although the mechanism of this was not clear. The patient has a long-lasting and intractable disease course, which may be caused by the complex autoantibodies involved. It is possible that the two autoantibodies, which developed at variable intervals via the epitope spreading phenomenon, exerted a ‘sum effect’, leading to the lack of response to conventional immunosuppressive therapy. Recently, a combination therapy of rituximab and IVIg was proven to arrest disease progression and prevent total blindness in patients with recalcitrant ocular MMP. In our case, the patient refused to receive additional treatments. Patients with ocular MMP may have serious visual impairments, even blindness, and may need more aggressive treatments. Therefore, accurate and fast diagnosis should be made using various immunofluorescence and IB techniques.