From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Accelerated access to innovative medicines for patients in need.

There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and this practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.

Legal foundations of adaptive licensing.

In April 2012, MIT's Center for Biomedical Innovation and the European Medicines Agency (EMA) cosponsored a workshop on legal foundations of adaptive pharmaceuticals licensing. Past and present attorneys from the US Food and Drug Administration (FDA), the EMA, and Health Sciences Agency Singapore (HSA) found that existing statutes provided authority for adaptive licensing (AL). By contrast, an attorney from Health Canada identified gaps in authority. Reimbursement during initial phases of adaptive approaches to licensing was deemed consistent with existing statutes in all jurisdictions.

Adaptive licensing: taking the next step in the evolution of drug approval.

Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.

Effectiveness of different footbath solutions in the treatment of digital dermatitis in dairy cows.

Three experiments were conducted to test the effectiveness of different footbath solutions and regimens in the treatment of digital dermatitis (DD) in dairy cows. During the study, groups of cows walked through allocated footbath solutions after milking on 4 consecutive occasions. All cows were scored weekly for DD lesion stage on the hind feet during milking. A "transition grade" was assigned on the basis of whether the DD lesions improved (1) or deteriorated or did not improve (0) from week to week. This grade per cow was averaged for all cows in the group. In experiment 1, 118 cows were allocated to 1 of 3 footbath treatments for 5 wk: (1) 5% CuSO(4) each week, (2) 2% ClO(-) each week, or (3) no footbath (control). The mean transition grade, and proportion of cows without DD lesions at the end of the trial were significantly higher for treatment 1 above (0.36, 0.13, and 0.11, respectively; standard error of the difference, SED = 0.057). In experiment 2, 117 cows were allocated to 1 of 4 footbath treatment regimens for 8 wk: (1) 5% CuSO(4) each week, (2) 2% CuSO(4) each week, (3) 5% CuSO(4) each fortnight, or (4) 2% CuSO(4) each fortnight. For welfare reasons, cows allocated to the weekly and fortnightly footbath regimens had an average prevalence of >60% and ≤25% active DD at the start of the trial, respectively. Significantly more cows had no DD lesions (0.53 vs. 0.36, respectively; SED = 0.049), and the mean transition grade of DD lesions was higher in the 5% compared with the 2% weekly CuSO(4) treatment (0.52 vs. 0.38, respectively; SED = 0.066). Similarly, significantly more cows had no DD lesions in the 5% compared with the 2% fortnightly CuSO(4) treatments (0.64 vs. 0.47, respectively; SED = 0.049). In experiment 3, 95 cows were allocated to 1 of 3 footbath treatments: (1) each week alternating 5% CuSO(4) with 10% salt water, (2) each week alternating 5% CuSO(4) with water, or (3) 5% CuSO(4) each fortnight (control). After 10 wk, more cows had no DD in the salt water treatment than in the control treatment (0.35 vs. 0.26, respectively; SED = 0.038), but levels of active lesions were higher for this treatment than in the other 2 treatments (0.17, 0.00, and 0.13, respectively; SED = 0.029). Treatment did not affect mean transition grade of DD lesions. In conclusion, CuSO(4) was the only footbath solution that was consistently effective for treatment of DD. In cases when DD prevalence was high, a footbath each week using 5% CuSO(4) was the most effective treatment.

Short communication: risk of severe heel erosion increased with parity and stage of lactation in freestall-housed dairy cows.

Heel erosion is the most prevalent hoof lesion in housed dairy herds, particularly in freestall facilities. It is associated with hoof contact with manure slurry and abrasive floors. The objective was to assess changes in the risk of heel erosion from the dry period to mid lactation in primiparous and multiparous dairy cows. Nineteen pregnant primiparous cows, 22 late-lactation multiparous cows (parity=3.2+/-1.4; days in milk=221+/-38), and 16 nonlactating, pregnant multiparous cows (parity=3.7+/-1.4) housed in a freestall barn with concrete flooring were followed until mid lactation. The hind hooves of all the cows were examined approximately every 7 wk and heel erosion was scored. Multiparous cows more likely had heel erosion than primiparous cows (odds ratio=11.0; 95% confidence interval=3.7, 32.7). Time relative to calving showed a significant quadratic effect, revealing that the risk of heel erosion increased more rapidly as lactation progressed. Survival analysis showed that multiparous cows had a higher relative risk of developing heel erosion than primiparous cows (hazard ratio=3.4). No cows improved between early and mid lactation, but 18 cows worsened. In conclusion, stage of lactation and parity were major risk factors for severe heel erosion in dairy cattle housed in freestalls.

Lipid content and fatty acid composition of the digital cushion of bulls offered different amounts of linseed.

Previous research suggests that the digital cushion, a shock-absorbing structure in the claw, plays an important role in protecting cattle from lameness. This study aimed to assess the degree to which nutritional factors influence the composition of the digital cushion. This involved quantifying lipid content and fatty acid composition differences in digital cushion tissue from cattle offered diets with different amounts of linseed. Forty-six bulls were allocated to 1 of 4 treatments, which were applied for an average of 140 +/- 27 d during the finishing period. The treatments consisted of a linseed supplement offered once daily on top of the basal diet (grass silage:concentrate) at 0, 400, 800, or 1,200 g of supplement/animal per day. For each treatment, the concentrate offered was adjusted to ensure that total estimated ME intake was constant across treatments. Target BW at slaughter was 540 kg. Legs were collected in 3 batches after 120, 147 and 185 d on experiment. Six samples of the digital cushion were dissected from the right lateral hind claw of each animal. Lipids were extracted and expressed as a proportion of fresh tissue, and fatty acid composition of the digital cushion was determined by gas chromatography. Data were analyzed by ANOVA, with diet, location within the digital cushion, and their interactions as fixed effects and fat content (grams per 100 g of tissue) as a covariate. Linear or quadratic contrasts were examined. The lipid content of digital cushion tissue differed between sampling locations (P < 0.001) but did not vary by treatment. There were quadratic responses to increasing linseed supplementation for several fatty acids. Although the overall proportion of C18:3n-3 (the most abundant fatty acid in linseed) did not differ (P < 0.33) by treatment, there was a quadratic influence of diet on total PUFA concentration (P = 0.003) and a linear increase in C18:3n-3 as a proportion of total PUFA (P = 0.01) in the digital cushion. This work demonstrates that dietary fatty acid composition influences the concentration of fatty acids incorporated in the digital cushion of cattle. Based on the large number of quadratic responses among the fatty acids, it appears there is a threshold amount of fatty acid incorporation in the digital cushion.

Effects of breed and production system on lameness parameters in dairy cattle.

The aim of the present study was to assess the effects of Holstein-Friesian (HF) and Norwegian (N) dairy cattle genotypes on lameness parameters in dairy cattle within different production systems over the first 2 lactations. Following calving, HF (n = 39) and N (n = 45) heifers were allocated to 1 of 3 systems of production (high level of concentrate, low level of concentrate, and grass-based). High- and low-concentrate animals were continuously housed indoors on a rotational system so that they spent similar amounts of time on slatted and solid concrete floors. Animals on the grass treatment grazed from spring to autumn in both years of the study, so that most animals on this treatment grazed from around peak to late lactation. Claw health was recorded in both hind claws of each animal at 4 observation periods during each lactation as follows: 1) -8 to 70 d postcalving, 2) 71 to 150 d postcalving, 3) 151 to 225 d postcalving, and 4) 226 to 364 d postcalving. Sole lesions, heel erosion, axial wall deviation, sole length of the right lateral hind claw (claw length), right heel width, and right lateral hind heel height were recorded as well as the presence of digital dermatitis. The N cows had lower (better) white line and total lesion scores than HF cows. Cows on the high- and low-concentrate treatments had better sole and total lesion scores than cows on the grass treatment. The HF cows had better locomotion scores than N cows. Breed and production system differences were observed with respect to claw conformation, including claw length, heel width, and heel height. Digital dermatitis was associated with worse sole lesion scores and interacted with production system to influence white line lesion scores and maximum heel erosion scores. This study shows that genetic, environmental, and infectious factors are associated with hoof pathologies in dairy cows.

Voluntary guidance for the development of tissue-engineered products.

Tissue Engineering is an emerging field of medical research in which there is tremendous activity. Many of these products rely on the use of a cellular component co-formulated with a natural or synthetic biomaterial. At this time, though, there are no consensus safety or efficacy standards for tissue-engineered products. We describe general approaches for assessment of the safety and efficacy of cell-based tissue-engineered products which will lead to reliable medical products for human use. This article provides a general summary of the factors that should be considered in the design and development of cell- and tissue-based products. Seven areas are considered: cell and tissue sourcing; cell and tissue characterization; biomaterials testing; quality assurance; quality control; and nonclinical testing and clinical evaluation. Factors relevant to these areas have been discussed to provide a set of recommendations on which development of products can be standardized. Where relevant, the discussion has been separated in each area to issues that are independent or dependent on cell source. Also, examples are provided of how these guidelines would be applied to two product types that represent somewhat extreme ends of the spectrum for tissue engineering applications. The first example is a product whose mechanism of action is to provide locally-acting structural repair or enhancement in vivo. The second example is a product whose mechanism of action involves systemically distributed physiologically or pharmacologically active products. In general, we have limited the discussion of product types to those that are implanted into the patient for relatively long periods of time. We believe that adoption of these voluntary guidelines would lead to products that are more consistent in quality and performance as well as more rapidly developed.

Immunoglobulin light and heavy chain isotypes in skin diseases: restricted distribution in bullous pemphigoid and linear IgA bullous dermatosis.

To assess the heterogeneity of immunoglobulins involved in various skin diseases, direct and indirect immunofluorescence studies of skin biopsies and sera, respectively, for kappa and lambda light chains, were performed. The anti-basement membrane zone (anti-BMZ) antibodies of patients with bullous pemphigoid showed a predominance of kappa light chains, and patients with linear IgA bullous dermatosis showed a predominance of one light chain that was sometimes kappa and sometimes lambda. The bullous pemphigoid autoantibodies were then studied for IgG subclass distribution; a predominance of IgG4 was found. Although other explanations are possible, the light chain restriction in bullous pemphigoid most likely reflects heavy chain restriction and preferential association of heavy and light chain isotypes. The basis of the heavy chain restriction is not apparent. The light chain restriction in linear IgA bullous dermatosis may represent a restricted idiotypic repertoire.

Characterization of antigens and antibody specificities involved in Heymann nephritis.

The present study was conducted to determine if Fx1A, a renal cortical extract used to induce Heymann nephritis, contains nephritogenic antigens in addition to the brush border-derived glycoprotein gp 330. Of 26 Lewis rats immunized with Fx1A, 24 developed abnormal proteinuria (greater than 20 mg/24 hr) by wk 10, whereas of 15 rats immunized with a partially purified gp 330 preparation (MVH), only one developed proteinuria. Immunofluorescence studies showed that all Fx1A rats developed large, diffuse, granular deposits along the glomerular basement membrane which stained brightly for IgG and C3; only 11 of the 15 MVH rats had definite deposits; in most rats, they were small and stained only moderately for IgG and faintly or not at all for C3. The Fx1A and MVH rats developed comparable levels of antibodies to MVH (gp 330) before the onset of proteinuria in Fx1A rats, after which serum IgG and antibody levels declined. In contrast, antibodies against soluble Fx1A antigens appeared earlier and rose more rapidly in Fx1A than in MVH rats. Larger amounts of IgG could be eluted from the glomeruli of Fx1A rats than from MVH rats. Eluates from the Fx1A rats contained antibodies that reacted with gp 330 and also a 95 kd antigen; the latter reactivity was not demonstrated in eluates of MVH rats. Immunoprecipitation studies showed that both gp 330 and the 95 kd antigen are components of normal glomeruli. The results show that immunization with Fx1A produces a more severe form of Heymann nephritis than does gp 330, and that Fx1A contains at least one nephritogenic antigen in addition to gp 330.

Studies with monoclonal antibodies against brush border antigens in Heymann nephritis.

The authors have prepared and studied three murine monoclonal antibodies that are reactive with antigens in brush border regions of proximal renal tubules of rats. Two of the antibodies, 14C1 and AG3, were derived from mice immunized with Fx1A and the third, 4H6, from a mouse immunized with isolated glomeruli obtained from rats with Heymann nephritis. Immunohistochemical, immunoelectron microscopic, and immunochemical studies showed that the three antibodies recognized different antigens. The antibody 14C1 recognized the previously described nephritogenic glycoprotein, gp 330, in microvillar brush border preparations, and reacted with material present on podocyte cell surfaces of normal rat kidneys, especially in coated pits, as well as with material in the glomerular deposits of rats with Heymann nephritis. The antibody 4H6 recognized a 110-kilodalton microvillar antigen and reacted with material in the glycocalyx of podocytes of normal glomeruli, but showed only equivocal reactivity with material in the deposits in Heymann nephritis. AG3 failed to immunoprecipitate a distinctive antigen in microvillar preparations and did not react with the glomeruli of normal rats or of rats with Heymann nephritis. All three antibodies reacted with epithelial cells in the intestine, epididymis, and placenta; 4H6 also reacted with thin loops of Henle as well as with endothelial cells or other cells in lung, lymphoid tissue, liver, and spleen. The results demonstrate that not all brush border antigens participate in Heymann nephritis and confirm that an antigen (gp 330) involved in the formation of glomerular deposits in Heymann nephritis is normally present on podocyte surfaces, especially in coated pits, but is not present in extracellular sites.

Lymphocyte activation antigens. I. A monoclonal antibody, anti-Act I, defines a new late lymphocyte activation antigen.

Lymphocyte activation entails a sequence of events identified by analyzing the time course of expression of various distinctive cell surface molecules on lymphocytes that appear early (before initiation of DNA synthesis), parallel with DNA synthesis and cellular proliferation, or late (after peak proliferation). In this study we present identification of a novel late lymphocyte activation antigen, Act I, utilizing a murine monoclonal antibody. Anti-Act I was identified in a fusion of NS1 with BALB/c spleen cells immunized with a human tetanus toxoid-reactive T lymphoblast line. Flow cytometry analysis shows that Act I antigen is present in markedly greater amounts on activated T and B lymphocytes than on resting, small peripheral blood lymphocytes. Act I expression by these lymphocytes is promoted by PHA, tetanus toxoid, or alloantigens and lags behind maximal thymidine incorporation by 1 to 2 days. Thymocytes can be triggered to express Act I antigen during maturation induced by PHA/T cell growth factor stimulation. In vitro, anti-Act I does not affect antigen- or lectin-stimulated T cell proliferation, T cell-mediated lymphocytotoxicity, or T cell growth factor-induced proliferation of T lymphoblasts. By immunoperoxidase analysis, Act I antigen is restricted to lymphoid tissue, staining many lymphocytes in the paracortex, germinal centers, and mantle zones of lymph nodes, tonsil, and spleen. By immunoprecipitation, the Act I antigen is a single band of 63,000 m.w. on reduced or nonreduced SDS gels. The distribution, size, time course, and functional correlates indicate that Act I is different from other known T cell activation markers detected with anti-Tac, OKT9, B3/25, OKT10, 4F2, CBL1, and anti-Ia-like antibodies. Although the function of Act I is still undetermined, it may serve as a useful marker of a late stage of activation in vitro and in vivo.

Association of CSF IgG concentration and immunoglobulin allotype in multiple sclerosis and optic neuritis.

The cerebrospinal fluid (CSF) and serum from 64 patients with multiple sclerosis (MS) and 47 patients with monosymptomatic optic neuritis (ON) were analyzed for the distribution of allotypic determinants on IgG and compared to similar samples from 51 patients with other neurological diseases (OND) as well as to serum samples from 97 healthy controls. The results indicate a significantly increased frequency of the haplotypes Gm a;g and Gm a,x;g among MS patients (P = 0.024) with an associated increase in relative risk for MS among individuals with the Gm a,(x);g haplotypes compared to those individuals without them (P = 0.014). Among MS patients, those with the Gm a,(x);g haplotypes had significantly higher CSF levels of IgG than those without (P = 0.016); levels of serum IgG did not covary with Gm haplotype. Two-way analysis of variance indicates that familial cases have significantly higher levels of CSF IgG than nonfamilial cases (P less than 0.001) and that familial cases with the Gm a,(x);g haplotypes have the highest CSF IgG levels (P less than 0.005). There was no correlation between Gm haplotype and CSF or serum IgG levels in patients with ON or OND. The allotype effects were independent of age at onset and duration of disease. In all patients, regardless of disease classification, the phenotypes found in serum samples were identical to those found in CSF samples. The data presented support the hypothesis that the etiology of MS has as one of its parameters an immunoregulatory/immunogenetic factor. The successful analysis of these various parameters will provide useful information not only about MS but also about general principles of human immune responsiveness.

Rabbit anti-human CSF IgG. I. Characterization of anti-idiotype antibodies produced against MS CSF and detection of cross-reactive idiotypes in several MS CSF.

Serum from rabbits injected with IgG prepared from the CSF of patients with multiple sclerosis were rendered anti-idiotypic by adsorption on sequential columns of pooled human gamma-globulin, free light chains and free heavy chains. Adsorbed antisera precipitated between 15% and 45% of the autologous ligand and were inhibited by autologous CSF and serum and F(ab')2 fragments prepared from serum IgG. Idiotypic cross-reactivities were detected among the CSF IgG of several MS patients using three of these antisera. Two antisera demonstrated low levels of cross-reactivity with CSF IgG obtained from two of six heterologous MS patients. The third antiserum detected highly cross-reactive idiotypic determinants in the CSF IgG of two family members both having MS.

Identification of a unique idiotype in cerebrospinal fluid and serum of a patient with multiple sclerosis.

Anti-idiotypic antibodies were prepared in mouse ascites fluid against the CSF-IgG of a patient with multiple sclerosis. After adsorption with pooled human IgG, the ascites fluid antibodies precipitated 20% of labeled autologous CSF IgG. By using a competitive radioimmunoassay, less than one microgram of unlabeled CSF IgG produced 50% inhibition of binding autologous 125I-labeled CSF IgG, whereas 50 micrograms of normal HIgG was not inhibitory. The idiotype could be found in both serum and CSF IgG and persisted over a 5-year period. The absolute concentration of idiotype in the CSF varied somewhat but remained from 4 to 10 times greater than that of the serum. One of 14 heterologous MS CSF was found to contain small amounts of inhibitory protein; eight CSF from patients with other neurologic diseases did not contain the idiotype.